Kenny-Caffey Syndromes, Osteocraniostenosis and Sanjad-Sakati Syndrome (FAM111A and TBCE)

Bone dysplasias with medullary stenosis of the tubular bones and congenital hypoparathyroidism: the dominant allelic family of FAM111A (Kenny-Caffey syndrome type 2 and osteocraniostenosis) and the recessive allelic family of TBCE (Sanjad-Sakati syndrome, Kenny-Caffey syndrome type 1 and neurological and muscular phenotypes)

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

The class brings together two genetic families that share primary hypoparathyroidism with hypocalcaemia and hyperphosphataemia and, to a variable degree, stenosis of the medullary cavity of the long bones. The dominant form, caused by heterozygous FAM111A variants, ranges from Kenny-Caffey syndrome type 2 (KCS2), compatible with adult life and usually with normal intelligence, to osteocraniostenosis or gracile bone dysplasia (GCLEB, OCS), which is lethal in the perinatal period [1–3]. The recessive form, caused by biallelic TBCE variants, includes hypoparathyroidism-retardation-dysmorphism syndrome (HRDS) or Sanjad-Sakati syndrome (SSS) and Kenny-Caffey syndrome type 1 (KCS1), which the recent literature regards as manifestations of the same disease, as well as two allelic phenotypes without hypoparathyroidism [4–7]. The third column of the table covers the diseases of two other tubulin-folding cofactors that act in the same complex as TBCE: TBCD encephalopathy and TBCB-related complicated spastic paraplegia, which have neither hypoparathyroidism nor bone dysplasia and enter the differential diagnosis of PEAMO [8–10].

1. Introduction

1.1. Original description and evolution of the concept

In 1966, Kenny and Linarelli described a mother and son with marked proportionate dwarfism, dense tubular bones with narrow medullary cavities and self-limiting episodes of hypocalcaemia with hyperphosphataemia, documented at 39 years of age in the mother and between the 1st and 15th week of life in the son; both had late closure of the anterior fontanelle and normal intelligence, and the mother measured 48 inches (about 122 cm) [2, 42]. Caffey published the radiological analysis of the same family in 1967, under the title of congenital stenosis of the medullary spaces of the tubular bones and calvaria in two proportionate dwarfs with transient hypocalcaemic tetany, and the pair of eponyms became attached to the entity [2, 43]. In the following decades, observations accumulated that established the phenotype: Boynton and colleagues (1979) showed that the refractive error is hypermetropia due to nanophthalmos and reported the only known autopsy of the pre-molecular era, in a patient who died at 19 years, with no identifiable parathyroid tissue and with calcifications of the basal ganglia, dentate nuclei, cerebrum and cerebellum; Lee and colleagues (1983) demonstrated inappropriately low parathyroid hormone (PTH) during spontaneous and induced hypocalcaemia; Fanconi and colleagues (1986) found undetectable PTH in two patients and a structurally abnormal PTH in a third; Majewski and colleagues (1981) documented mother-to-child transmission [2, 43].

1.2. The recessive form and Sanjad-Sakati syndrome

In 1992, Franceschini and colleagues described two siblings with the radiological picture of Kenny-Caffey born to normal consanguineous parents, and proposed an "autosomal recessive variant"; in 1997, Khan and colleagues reported 16 children from six consanguineous Bedouin sibships in Kuwait with marked growth retardation, small hands and feet, hypoparathyroidism, cortical thickening with medullary stenosis, absence of the diploic space and psychomotor delay, without macrocephaly [4]. In parallel, Sanjad, Sakati and colleagues presented in 1988, in abstract form, and published in 1991 twelve Saudi infants with congenital hypoparathyroidism, severe intrauterine and postnatal growth restriction, seizures and dysmorphism, while Richardson and Kirk (1990) described eight children from the Middle East with the same picture [5, 44]. The mapping of both forms to 1q42-q43, with a common ancestral haplotype (Diaz 1998; Parvari 1998; Kelly 2000), anticipated the demonstration by Parvari and colleagues, in 2002, that TBCE variants, above all an in-frame 12-base-pair deletion, cause both HRDS and recessive KCS [4, 5, 45].

1.3. Osteocraniostenosis

Kozlowski and Kan and Maroteaux and colleagues described in 1988 fetuses and newborns with thin, fragile bones, craniofacial dysmorphism and perinatal death; in 1994, Verloes and colleagues brought together three fetuses and earlier cases under the name osteocraniostenosis, with extremely thin and dense diaphyses, flared metaphyses, mild micromelic dwarfism, brachydactyly, microphthalmia, aniridia, cloverleaf skull and splenic hypoplasia [3, 28, 46]. Elliott and colleagues (2006) argued that the cloverleaf skull results from hypomineralisation of the cranial bones and not from true craniosynostosis, and proposed the term osteocraniosplenic syndrome; Spear (2006) confirmed that craniostenosis had been reliably documented in only two patients, most of whom had widened sutures [3].

1.4. Discovery of FAM111A and reclassifications

In 2013, Unger and colleagues found heterozygous FAM111A variants, all de novo in the seven families with parental DNA, in five patients with dominant KCS and five with OCS; the same variant arose in four unrelated patients with KCS and another in two with OCS, which established the two conditions as allelic diseases of different severity [12, 47]. Isojima and colleagues confirmed, in four Japanese patients, the de novo recurrence of p.Arg569His as a KCS2 hotspot [48]. OMIM then numbered the dominant form as KCS type 2 (127000) and the recessive form as KCS type 1 (244460), keeping HRDS in a separate entry (241410) [2, 4, 5]. This nomenclature is disputed: the bone dysplasia atlas and Rosato and colleagues consider that calling the recessive form "Kenny-Caffey" perpetuates a historical error, since the original description was dominant, and that the TBCE form would be better named Sanjad-Sakati syndrome [28, 43]. The 2023 revision of the nosology of genetic skeletal disorders adopted this position, naming the FAM111A form "Kenny-Caffey syndrome, dominant, FAM111A-related" and the TBCE form "Sanjad-Sakati syndrome, recessive, TBCE-related" [1, 49]. In the text that follows, KCS2 and OCS are used for the FAM111A family, and SSS/KCS1 for the TBCE family, with the caveat that KCS1 and SSS share the same allele and overlap clinically [7, 18].

1.5. Operational definitions

KCS2 is defined by the combination of proportionate short stature of postnatal onset, a large anterior fontanelle with late closure, cortical thickening with stenosis of the medullary cavity of the long bones, ocular and dental anomalies and primary hypoparathyroidism, with a heterozygous pathogenic FAM111A variant [1, 21]. OCS is defined by the severe prenatal form of the same spectrum: intrauterine growth restriction, cloverleaf skull with deficient ossification, gracile long bones with abrupt metaphyseal flaring, thin ribs with thoracic and pulmonary hypoplasia and splenic a/hypoplasia [1, 22]. SSS/KCS1 is defined by the combination of severe intrauterine and postnatal growth restriction, congenital hypoparathyroidism, microcephaly, characteristic dysmorphism and developmental delay, with biallelic TBCE variants; osteosclerosis with medullary stenosis and susceptibility to bacterial infections, which served to separate KCS1, also occur in pedigrees with an HRDS phenotype [6, 23, 24]. PEAMO is defined by a neurodegenerative encephalopathy with onset in infancy or early childhood, with distal amyotrophy due to motor neuronopathy, pyramidal and cerebellar signs, optic atrophy, thin corpus callosum and cerebellar atrophy, without hypoparathyroidism, dysmorphism or growth restriction, and with biallelic TBCE variants; the hypomorphic allele p.(Ile155Asn) was present in all patients described by Sferra, by Battini and in the eight new patients of Sartorelli [27, 30, 31, 35]. No consensus clinical criteria have been published for any of these entities, and diagnosis rests on the combination of phenotype and genotype [1].

1.6. The tubulin-folding cofactor diseases

In September 2016, three papers published in the same issue of the American Journal of Human Genetics linked two tubulin cofactors to neurological diseases: Miyake and colleagues described eight children from four families (two Japanese, one Malaysian Chinese and one Iraqi Jewish) and Flex and colleagues seven children from five families, all with biallelic TBCD variants, while Sferra and colleagues defined PEAMO due to TBCE [30, 32, 33]. Edvardson, Pode-Shakked and Ikeda added 11 patients between 2016 and 2017, and Grønborg described in 2018 eight patients from the Faroe Islands homozygous for a founder variant [19, 50–52]. OMIM designated the TBCD disease as early-onset progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT, 617193) [8]. In 2025, Bratman Morag and colleagues described ten patients from eight Ashkenazi Jewish families homozygous for a TBCB variant, and OMIM created entry 621382 for neurodevelopmental disorder with behavioural abnormalities and childhood-onset spastic paraplegia (NEDBSPG) [9, 36]. The genes for the cofactors TBCA and TBCC remain without an associated Mendelian disease in OMIM [33].

PEBAT is defined by an autosomal recessive encephalopathy with severe psychomotor delay apparent at birth or in infancy, profound intellectual disability, absent or minimal language, epilepsy, hypotonia or spasticity that prevent walking in most, progressive microcephaly and, on imaging, cerebral and cerebellar atrophy, thin corpus callosum and secondary hypomyelination, with biallelic TBCD variants [8]. NEDBSPG is defined by mild global delay from infancy, behavioural abnormalities (above all autism spectrum disorder), mild intellectual disability in some patients and slowly progressive spastic paraplegia with onset at the end of the first decade, with homozygosity for a TBCB variant; OMIM also classifies it as a complicated form of spastic paraplegia [9]. There are no consensus clinical criteria for either of the two [15, 16].

2. Molecular Genetics and Pathophysiology

2.1. FAM111A: structure, expression and function

FAM111A is located at 11q12.1 (GRCh38 11:59,142,856–59,155,039) and encodes a 611-amino-acid protein with a C-terminal trypsin-like serine peptidase domain, which contains the conserved catalytic triad of histidine, aspartate and serine [1, 12]. Initial cloning predicted 628 amino acids and showed the highest expression in adult spleen, followed by kidney, lung, ovary, liver and pancreas, and low expression in muscle, heart, testis and brain; in cycling cells, the RNA and protein are minimal in G0 and maximal on the way to G2/M [12]. The protein is located in the nucleus and cytoplasm, binds to the large T antigen of the SV40 virus and acts as a restriction factor for that virus and for vaccinia virus, in part by disrupting the nuclear pore complex through its protease activity [12, 53]. Studies in 2020 identified the native function: FAM111A is a protease that binds single-stranded DNA, cleaves covalent DNA-protein crosslinks during DNA synthesis, including topoisomerase 1 adducts and PARP1-DNA complexes trapped by PARP inhibitors, is required for PCNA loading at replication sites and protects replication forks [53, 54]. Cell lines lacking FAM111A have almost normal viability, but greater sensitivity to agents that induce replication stress [1]. Expression in bone and in the parathyroids supports the hypothesis of a role in skeletal development, linear growth and the development or regulation of the parathyroid glands, although the link between the replicative function and the phenotype has not been established [1, 55].

2.2. Disease mechanism in the FAM111A family

All variants associated with KCS2 or OCS described up to 2022 are single amino acid substitutions or in-frame single amino acid deletions, clustered in the serine peptidase domain and around the autocleavage site [1, 7]. Haploinsufficiency is unlikely: null alleles exist in population databases and have not been identified in patients, and analysis of deletions and duplications of exons or of the whole gene has never revealed a causal variant [1]. Hoffmann and colleagues showed that FAM111A protease activity impairs cellular fitness and that the disease variants amplify it, increasing intra- and intermolecular autocleavage and causing cytotoxicity dependent on catalytic activity; hence the proposal of a dominant gain-of-function mechanism, which GeneReviews retains as a hypothesis and not as an established mechanism [1, 56]. Unger and colleagues had observed, in a structural model, that the affected residues are not located near the active site but in a segment on the surface of the protein, which suggested a disturbance of the interaction with as yet unknown partners [47]. Abraham and colleagues modelled p.Ser541Tyr, which affects the probable catalytic serine residue, at a more internal point than p.Arg569His, and Djordjevic Milosevic and colleagues proposed, on the basis of p.Ser541Pro, that variants of the catalytic triad (His385, Asp439, Ser541) would disturb parathyroid function more profoundly [55, 57]. In 2026, Wu and colleagues described a frameshift variant, c.405delA p.(Glu136Serfs*3), in an 11-year-old boy with a "KCS2-like" phenotype, associated in vitro with osteoclast necroptosis and release of inflammatory cytokines; this is an isolated observation, which contrasts with the argument from the absence of truncating variants and does not, in itself, change the interpretation of truncating FAM111A variants found on panels [1, 58].

2.3. FAM111A variant spectrum and nomenclature

The MANE Select transcript is NM_001312909.2 (NP_001299838.1); the early literature used NM_001142519.1, with the same numbering in the coding region for the recurrent variants [13, 48, 59]. The table brings together the variants normalised in VariantValidator and the phenotype in which they were described.

The in-frame three-nucleotide deletion described by OMIM as 1026_1028delTTC with "deletion of serine 342" normalises, by the most-3′ position rule, to c.1026_1028del p.(Ser343del), the same notation used in the 2026 Chinese report (c.1020_1022delTTC p.Ser343del in another numbering); the historical designation should be read with this conversion [12, 13, 61].

2.4. Genotype-phenotype correlation, penetrance and expressivity in the FAM111A family

The first series suggested distinct variants for KCS2 and OCS, but GeneReviews concludes that there is no established correlation and that the genotype does not reliably predict KCS2 or OCS [1, 28]. Two observations reinforce this caveat: p.Pro527Thr, first described in an infant with GCLEB who died at 8 months, was found in a living patient with KCS2; and carriers of the p.Arg569His hotspot show great heterogeneity, from severe neonatal hypocalcaemia to diagnosis at 18 years or hypocalcaemia arising during growth hormone treatment [7, 29]. In the review by Schigt and colleagues, the only significant difference between the hotspot and the other variants was chronic kidney disease, more frequent with non-recurrent variants (6/8 versus 1/8), with the caveat that four of the six patients were from the same family [7]. Penetrance is complete in the families described, and expressivity is variable within families [1, 7]. No other germline allelic diseases of FAM111A are known [1].

2.5. TBCE: structure and function

TBCE is located at 1q42.3 and encodes tubulin-folding cofactor E, a chaperone involved in the second step of the β-tubulin folding pathway: it binds to the β-tubulin–cofactor D intermediate and, with cofactor C, releases α/β heterodimers competent for polymerisation; it also regulates heterodimer dissociation and the maintenance of the neuronal microtubule network and of the mitotic spindle [6, 26]. It has about 30% identity with the yeast pac2 protein and a CAP-Gly domain that binds α-tubulin, where the SSS/KCS1 variants are located [6, 7]. In the mouse, Tbce accumulates in the Golgi apparatus of motor neurons and controls axonal routing of tubulin; the pmn mutant (p.Trp524Gly of murine Tbce) develops progressive motor neuronopathy with retrograde axonal degeneration from 2 weeks and dies between 4 and 6 weeks, in addition to hearing loss and sensory neuropathy [6].

2.6. TBCE mechanism and variant spectrum

Parvari and colleagues showed, in patient fibroblasts and lymphoblastoid lines, lower microtubule density at the organising centre, disturbed polarity and alterations of microtubule-dependent organelles, such as the Golgi and late endosomes, classifying HRDS and KCS1 as chaperone diseases of the tubulin assembly pathway; the endocrine consequence is congenital aplasia or hypoplasia of the parathyroids [26, 45]. The founder allele NM_003193.5:c.155_166del p.(Ser52_Gly55del) (NC_000001.11:g.235401557_235401568del), an in-frame 12-base-pair deletion in exon 3, was found in the homozygous state in all of the more than 50 patients from the Middle East with HRDS studied by Parvari and colleagues, was absent from more than 350 Arab control chromosomes, and was the only variant in the 68 genotyped patients of the Gulf registry [6, 13, 18]. In a Belgian family, compound heterozygosity for c.66_67delAG (frameshift) and c.1113T>A p.(Cys371Ter) showed that cryptic translation initiation at out-of-frame AUG codons can generate functional polypeptides and explain the survival of patients with apparently null alleles [6].

2.7. Allelic TBCE phenotypes without hypoparathyroidism

PEAMO (OMIM 617207) was described by Sferra and colleagues in patients from Southern Italy homozygous for p.(Ile155Asn): early-onset progressive encephalopathy with distal spinal amyotrophy and optic atrophy; the cells show less polymerised α-tubulin, reduced nucleation, very slow repolymerisation, a less compact Golgi and abnormal mitotic spindles, and the allele is hypomorphic [6, 30]. Sartorelli and colleagues gathered, in 2026, 335 patients with TBCE variants (13 from their own cohort and 322 from the literature): SSS accounted for 85% and the neurodegenerative phenotype for 5%, the latter ranging from spastic-ataxic tetraparesis with optic atrophy and distal axonal motor neuropathy to complex spastic paraparesis, with progressive thinning of the corpus callosum, cerebro-cerebellar atrophy, white matter changes and possible iron accumulation in the deep grey nuclei [27]. MRSG (OMIM 621734) was described in 2025 in seven Slavic patients from six Russian families and in three Polish and Ukrainian patients, carrying NM_003193.5:c.100+1G>A in the homozygous or compound state; cryptic translation from out-of-frame codons restores the reading frame from exon 4 and explains a milder phenotype than SSS or PEAMO, with rigid spine, scoliosis, male hypogonadotropic hypogonadism and, in one report, eosinophilia, neutropenia and nocturnal hypoxaemia [6, 64]. These forms confirm that the residual dose of functional TBCE determines whether the phenotype is endocrine-skeletal, neurodegenerative or muscular.

2.8. Genotype-phenotype correlation in the TBCE family

The same founder allele, in the homozygous state, produced the KCS1 phenotype (medullary stenosis, calvarial osteosclerosis and susceptibility to bacterial infections) in 8 pedigrees with 13 affected individuals and the HRDS phenotype in 17 Saudi pedigrees (27 affected) and 9 Israeli pedigrees (25 affected); the presence of patchy osteosclerosis in some Saudi patients and of deaths from sepsis in some Bedouins with HRDS indicates variable expression by pedigree and not two diseases [6]. Schigt and colleagues and Almutair and colleagues conclude that KCS1 and SSS are probably manifestations of the same disease [7, 18]. Courtens and colleagues described a girl with an HRD picture without a TBCE variant and with normal protein, which suggests locus heterogeneity [5].

2.9. Pathophysiology of the phenotype

In both families, the endocrine defect is primary hypoparathyroidism: no parathyroid tissue was found at the 1979 autopsy, and PTH is low or undetectable during hypocalcaemia [2, 43]. The absence of PTH reduces distal tubular calcium reabsorption, renal phosphate excretion and renal 1α-hydroxylation of 25-hydroxyvitamin D, which explains the triad of hypocalcaemia, hyperphosphataemia and low calcitriol and justifies why native vitamin D does not replace the active metabolites [26, 65]. Hyperphosphataemia and a high calcium-phosphate product favour ectopic calcifications in the basal ganglia, the lens and the kidney; treatment, by normalising calcium without PTH, increases calciuria and contributes to nephrocalcinosis [1, 34]. Hypomagnesaemia accompanies the picture, without being the main symptom [66]. In the FAM111A family, hypomagnesaemia is as frequent as in the TBCE family (77% in both) and renal magnesium wasting has been described, whereas hypercalciuria before treatment is rare (9% versus 85% in KCS1), which suggests that the hypocalcaemia of KCS2 may have a component that is not exclusively parathyroid; patients with KCS2 and normal PTH have been described [7]. Saudubray classifies TBCE among the disorders of cytoskeleton-dependent cellular trafficking, with bone, endocrine and reproductive expression [67]. In the TBCE family, cytoskeletal impairment explains the multisystem involvement: hypoplasia of the adenohypophysis and corpus callosum, pituitary deficiencies, developmental delay, immune abnormalities and, in the hypomorphic forms, neuronal degeneration [5, 18, 27]. Medullary stenosis with apparently thickened cortex reflects a defect of diaphyseal modelling; Boynton noted that the cortex may not be truly thickened and that the narrow medulla creates the radiological impression of thickening [2].

2.10. Mechanism of the hypomorphic p.(Ile155Asn) allele in PEAMO

TBCE has 527 amino acids, with an N-terminal CAP-Gly domain that binds α-tubulin, nine tandem leucine-rich repeats (LRR) and a C-terminal ubiquitin-like domain, possibly involved in proteasomal degradation of α-tubulin [30]. The Ile155 residue is conserved in orthologues and, in the homology model of the LRR domain (residues 123–348), forms part of the hydrophobic core that stabilises the second repeat; substitution by a hydrophilic asparagine predicts disorganisation of that repeat and of domain folding [30]. In patient fibroblasts, the amount of TBCE was reduced, with normal messenger RNA in the homozygote and halved in the compound heterozygote, in whom the c.924del allele was not detectable in complementary DNA, which indicates nonsense-mediated decay; the reduction in protein was more marked in the latter [30, 31].

Total α-tubulin did not differ from controls, but the polymerised fraction and detyrosinated tubulin, a marker of stable, long-lived microtubules, were decreased [30]. After depolymerisation with nocodazole, microtubules in control cells began to repolymerise at 10 minutes and formed extensive structures at 30 minutes, whereas in patient cells repolymerisation was delayed, sparse and disorganised, above all in the compound heterozygote; the Golgi apparatus lost compaction, in parallel with reduced nucleation of Golgi-derived microtubules, and mitotic spindles were asymmetrical, with irregular asters [30]. Tail fibroblasts from the pmn mouse showed the same reduction in Tbce and in polymerised α-tubulin [30].

The difference between PEAMO and SSS is attributed to the amount of residual protein: in SSS and KCS1 the protein is practically absent, whereas the p.(Ile155Asn) allele preserves some TBCE; Sferra and colleagues interpret PEAMO as a partial loss of function that mainly affects neurons, which depend on microtubules for axonal transport, and compare it with ASAH1, in which hypomorphic alleles cause spinal muscular atrophy with progressive myoclonic epilepsy and alleles that abolish enzyme activity cause Farber disease [30]. The same authors found no explanation for the absence of neurodegeneration in SSS, in which the loss of function is greater [30]. In the pmn mouse, loss of axonal microtubules begins in the distal portion of the phrenic and sciatic nerves and progresses proximally, Tbce disappears from the Golgi of motor neurons and Schwann cells and axonal routing of tubulin from the Golgi fails; transgenic complementation with normal Tbce complementary DNA restored the normal phenotype [31]. The brain iron accumulation observed in patients in the second decade is not part of the neuropathology described in the pmn mouse [30].

The combination of the hypomorphic allele with a null allele lowers the protein even further and has been associated with more severe forms: Sferra's compound heterozygote had signs from birth and never acquired sitting, and Battini's patient, also compound heterozygous for p.(Ile155Asn) and c.924del, had earlier onset and a more severe course than most homozygotes, with white matter involvement [30, 35]. The variant has a founder effect: the families came from the Naples metropolitan area and the island of Ischia and shared a haplotype of about 0.5 Mb around TBCE [30].

2.11. TBCD and PEBAT encephalopathy

TBCD encodes tubulin-folding cofactor D, a protein of 1192 amino acids and about 133 kDa, formed mainly of antiparallel α-helices in armadillo/HEAT repeats, with a C-terminal TFCD_C domain; it is expressed in all tissues, with the highest expression in fetal and adult brain, heart and skeletal muscle [14, 32, 33]. TBCD captures GTP-bound β-tubulin and, with the GTPase ARL2, TBCE and TBCC, assembles and disassembles the α/β heterodimer; overexpression of TBCD depolymerises microtubules, and binding to ARL2 inhibits this effect [14, 33]. The cryo-electron microscopy structures of 2025 and 2026 showed that TBCD, TBCE and ARL2 form a heterotrimeric cage (TBC-DEG) around the heterodimer, in which TBCD envelops β-tubulin and TBCE extends along α-tubulin, and that rotation of TBCE, driven by the GTPase cycle of ARL2 and regulated by TBCC, delivers α-tubulin to, or removes it from, the β-tubulin held by TBCD [10, 68]. TBCD is also located at the centrosome and is required for microtubule nucleation and mitotic spindle organisation [33].

Most pathogenic variants are missense variants distributed along the protein, with a minority of truncating and splicing variants; Grønborg counted 21 different variants in 2018 (17 missense, three splicing and one nonsense) [19]. Functional studies showed a variable reduction of protein in fibroblasts (to about 10% with p.(Ala475Thr) and 40% with p.(Ala586Val) in the Edvardson series), instability of the mutant proteins with accelerated decay after inhibition of protein synthesis, selective loss of β-tubulin binding with NM_005993.5:c.1121C>T p.(Thr374Met) and NM_005993.5:c.1130G>A p.(Arg377Gln), and reduced binding to ARL2, TBCE and β-tubulin for most of Miyake's variants; in Drosophila, the mutant human proteins corrected the axonal defects of tbcd-null olfactory projection neurons less well than the normal protein, which confirms loss of function [32, 33, 50]. Unlike the hypomorphic TBCE allele in PEAMO, fibroblasts with TBCD variants have less soluble tubulin, more polymerised tubulin and accelerated repolymerisation after nocodazole, that is, a shift towards faster-growing and more stable microtubules, with disorganised mitotic spindles, fewer asters and larger centrosomes, without a change in proliferation rate [33]. Knockdown of Tbcd by RNA interference in the mouse brain in utero disturbed the proliferation and radial migration of cortical cells, and knockdown in zebrafish reproduced features of the disease [50, 51]. Miyake proposed that microtubule disorganisation impairs axonal transport of mitochondria, and the autopsy of one patient showed Purkinje cells with cactus formations and somatic sprouts, findings described in Menkes disease and in mitochondrial diseases [32].

Table sources: notation normalised in VariantValidator from the NM_005993.4 of the publications (the c. numbering coincides in versions .4 and .5) [13]. Edvardson's p.(Ala586Val) variant is described only in protein notation in the abstract consulted [50].

Severity is related to residual function. Patients with alleles that preserve some binding to partners, such as p.(Pro937Arg) or p.(Thr374Met), had milder forms, and carriers of a truncating allele with a strong-effect missense variant, or of alleles that reduce the protein to almost nothing, such as homozygous p.(Pro1122Leu) and the Faroese variant, had the most severe forms [19, 32, 33]. Flex predicted that complete loss of function would cause an even more severe neurodevelopmental phenotype [33]. The correlation is not absolute: homozygosity for p.(His77Arg) was described with severe encephalopathy in one family (Elmas and colleagues, cited by Quitmann) and with a mild phenotype, with absences and slight delay, in another, and Aynekin attributes the difference to modifier genes or epigenetic factors [37, 69]. Mild phenotypes with autism spectrum disorder and occasional tonic-clonic seizures controlled with antiseizure medications have been described in three patients from three families with compound variants, as has a distal motor neuronopathy of juvenile presentation in a 22-year-old woman [71, 72]. A heterozygous deletion of exons 28 to 39 in trans with a point variant shows that copy number variations also cause the disease [37].

2.12. TBCB and complicated spastic paraplegia

TBCB encodes tubulin-folding cofactor B, which binds to the α-tubulin folding intermediates released by the cytosolic chaperonin and, together with TBCE, regulates assembly and dissociation of the α/β heterodimer and axonal growth [16, 36]. The only disease-associated variant is NM_001281.3:c.589T>A p.(Tyr197Asn) (NC_000019.10:g.36125492T>A), found in the homozygous state in all ten published patients [9, 13, 36]. Fibroblasts from one patient had less TBCB, with normal cytoplasmic localisation alongside α-tubulin; in yeast, the orthologous ALF1 mutation (p.Phe196Asn) increased sensitivity to benomyl, a microtubule depolymeriser, and was only partially corrected by the mutant gene; in Drosophila, the homologous variant introduced by CRISPR/Cas9 caused semi-lethality, reduced longevity and reduced locomotor activity, and knockdown of the gene in neurons reduced climbing ability and survival [9, 36]. These results indicate partial loss of function; expression of the mutant human protein in yeast lacking ALF1 increased sensitivity to the depolymeriser, which, in that system, also suggests a dominant-negative effect [9]. As all patients share the same variant, the phenotype of other TBCB alleles is unknown [16].

3. Clinical Spectrum and Manifestations by System

3.1. Overview and data sources

The clinical data come from case series and from three syntheses: the GeneReviews table with 35 patients with FAM111A variants published between 2013 and 2023 (22 KCS2 and 13 OCS), the systematic review by Schigt and colleagues with 205 genetically confirmed patients (175 KCS1/SSS and 30 KCS2, literature up to December 2021) accompanied by their own cohort of 10 patients with KCS2, and the international registry of 135 patients with SSS from eight centres in Saudi Arabia, Oman and Kuwait, collected between 2021 and 2024 [1, 7, 18]. The denominators vary because each feature was described in only some of the patients; the percentages refer to the patients assessed for each feature and almost always include treated patients.

Table sources: [1, 7].

3.2. Kenny-Caffey syndrome type 2 (FAM111A)

Growth and proportions. Most are born at term with appropriate weight; intrauterine growth restriction is uncommon and short stature becomes established in the first year of life, with heights between -2.6 and -8.2 standard deviations and adult stature between 122 and 152 cm [1, 43]. Proportions are as a rule normal, with small hands and feet; about one in four patients with data had mild disproportion in the systematic review (10/13 proportionate) [7, 43]. Bone age is normal or delayed (delayed in 3/6) [7, 43]. Growth hormone deficiency has been described in three Korean and Japanese patients and in 4/11 patients tested in the systematic review, with low IGF-1 in 3/8; causality has not been demonstrated, and the response to growth hormone treatment is limited [1, 7, 55].

Skull and face. The macrocephaly is relative, resulting from very short stature with a preserved head circumference; the anterior fontanelle is large and closes late, and the calvaria has no diploic space [1, 21, 43]. Craniosynostosis, mainly basal, produces a V-shaped orbital roof and, in adolescents, a "beaten copper" appearance of the calvaria [1, 43]. The face is triangular, with a prominent forehead (17/19), short palpebral fissures (11/18), deep-set eyes, midface retrusion, a short nose with a narrow bridge and micrognathia (10/16) [1]. Microtia, a lacunar appearance of the skull and Arnold-Chiari malformation have been described in isolated cases [59].

Skeleton. The radiological hallmark is stenosis of the medullary cavity of the tubular bones with normal or thickened cortex and diaphyses of reduced diameter, with relative flaring of the metaphyses; the epiphyses and metaphyses are not affected, and the femoral neck may be in valgus [43]. In young children the stenosis may not be evident: in the patient of Abraham and colleagues, the neonatal radiograph was inconclusive and the stenosis was only recognised at 2 years [55]. In the cohort of Schigt and colleagues, two female carriers of p.Arg569His had no cortical thickening, one with gracile bones without medullary stenosis [7]. Fractures are not part of KCS2 [1]. In adults, the Chinese twins followed for more than 20 years developed severe torticollis and scoliosis, which suggests an age-dependent vertebral phenotype; rigid spine, coxa valga, genu and ankle valgus, hypermobility and polysyndactyly have also been described [1, 73].

Endocrine and mineral metabolism. Hypoparathyroidism manifests in most before 2 months, usually in the neonatal period, with hypocalcaemic seizures or tetany; severity is variable and most need calcium and active vitamin D for life [1]. The natural history includes self-limiting episodes (the original description spoke of "transient" hypocalcaemia), late presentations at 18 years or during growth hormone treatment at 8 years, and patients with normal PTH [2, 7, 29]. In Franceschini's review of 24 cases (1992), symptomatic hypocalcaemia occurred in 18/21 with onset between the first days and the fourth decade [2]. Hypomagnesaemia accompanies hypocalcaemia in about three quarters of patients, and hypercalciuria before treatment is rare [7]. Hypothyroidism was recorded in 3/4 patients with data [7].

Eyes. More than 80% have refractive errors, above all high hypermetropia due to nanophthalmos, corrected with lenses; microphthalmia, pseudopapilloedema (sometimes interpreted as pseudotumour cerebri), tortuous retinal vessels, corneal and retinal calcification, maculopathy, aniridia and glaucoma are described [1, 2, 7, 43]. Cataracts have been described in adults aged 20 and 40 years and in children with hypocalcaemia (congenital cataracts in a 6-year-old girl) [1, 2]. Nanophthalmos may be complicated by uveal effusion syndrome with serous retinal detachment, as in a 13-year-old girl with +17 and +15 dioptres [74].

Teeth. More than 60% have dental anomalies: oligodontia or hypodontia (agenesis in 50% in the review), thin or hypoplastic enamel, extensive caries, retention of the deciduous dentition, delayed eruption and loss of the permanent dentition before 40 years, with frequent use of dentures [1, 7, 73].

Nervous system. Development and cognition are normal in the great majority [1]. Basal ganglia calcifications are the most frequent imaging finding (5/10), and there are diffuse cerebral and cerebellar calcifications in long-standing cases [1]. In the systematic review, 5/24 patients with KCS2 had intellectual disability, including three from the Dutch cohort and Brazilian patients with microcephaly or maculopathy, which brings some of the cases closer to the TBCE phenotype [7, 75, 76].

Kidney. Nephrocalcinosis has been described in treated adults and in 4/10 patients in the review [1, 7]. Schigt and colleagues identified chronic kidney disease in 6 of 10 patients in their cohort, from three families, with stages G2 to G3b, end-stage kidney failure in a man who died at 77 years and kidney transplantation at 59 years in a daughter, most without nephrocalcinosis or hypercalciuria; the authors regard it as a new feature, possibly age-dependent and not explained by treatment alone [7].

Gonads and fertility. Microorchidism, a small penis, delayed puberty and subfertility are frequent in men; Hoffman and colleagues described microorchidism with elevated FSH and normal testosterone, and the only histology showed Leydig cell hyperplasia with preserved spermatogenesis [2, 43]. The first documented paternal transmission, in a Dutch family in which the father had eight children, four of them with short stature, shows that not all men are infertile; in women, agenesis of one ovary with mild ovarian insufficiency and labial fusion have been described [7].

Other. High-pitched voice (four patients), hearing loss, anaemia (50% in the review), neutropenia, eosinophilia and raised IgE, neonatal liver disease and severe infections in some patients; sepsis was the cause of death in 2 of 6 patients with reported infections [1, 2, 7].

Life expectancy. On the available evidence, life expectancy in KCS2 is normal; there are patients known in the sixth decade and a man who died of kidney failure at 77 years [1, 7, 43].

3.3. Osteocraniostenosis (gracile bone dysplasia, FAM111A)

OCS manifests before birth. In the review by Rosato and colleagues, when ultrasound was performed, cloverleaf skull was observed in 11/17 pregnancies, intrauterine growth restriction in 15/17, limb shortening in 16/17 and intrauterine fractures in 7/17, most already visible at 20 weeks; micrognathia with retrognathia and deficient cranial ossification are recognisable at the same age [1, 28]. At birth, the face, sometimes disfigured by hydrops, shows temporal bossing, blepharophimosis, a small nose, short philtrum, small mouth and micrognathia, with dysplastic ears and microphthalmia, coloboma, aniridia or cataracts [3, 46]. The limbs are moderately short, with short fingers and tiny nails, and the distal phalanges are poorly ossified [46]. Radiologically, the tubular bones are very thin and relatively dense, with abrupt "drumstick" metaphyseal flaring, the ribs and clavicles are thin and irregular, there is platyspondyly and underdeveloped lower ilia, and fractures at birth are frequent [28, 46]. Splenic a/hypoplasia is present in most (14/19 in the review), sometimes with extramedullary haematopoiesis [1, 28]. Micropenis, female genital hypoplasia and hydrocephalus have been described [1, 3, 12].

Pulmonary hypoplasia due to a small thorax is the main cause of death; most die in the first hours (a preterm infant of 32 weeks lived 25 minutes), and survivors need intensive respiratory support [1, 46]. Hypocalcaemia due to hypoparathyroidism is present in all assessed patients who survive the perinatal period (5/5 in Rosato's review) [28]. The longest reported survival was 21 months (a Swedish boy with shunted hydrocephalus, seizures, bone fragility, liver disease and developmental delay), and other infants died at 3 days, 25 days, 2 months and 8 months [1, 12]. Histology shows an irregular growth plate, with short, disorganised columns of pleomorphic chondrocytes and pseudocolumns, and neuropathological examination of a 21-week fetus revealed necrosis and calcification of the basal ganglia and thalamus [3, 28].

3.4. Sanjad-Sakati syndrome and Kenny-Caffey syndrome type 1 (TBCE)

Growth. In the Gulf registry, term newborns weighed on average 2.03 kg (-3.3 standard deviations), measured 43.5 cm (-3.0) and had a head circumference of 32.5 cm (-1.7); poor weight gain followed in the first year and, from 1 year, a stable stature between -7 and -8 standard deviations, with a body mass index between -1 and -3 [18]. A 21-year-old adult female patient measured 125 cm [18].

Dysmorphism. Deep-set eyes (95.4%), low-set ears (90.8%), beaked nose (85.4%), small hands and feet (85.0%), depressed nasal bridge (85.0%), thin lips (84.3%), frontal bossing (79.2%), micrognathia (78.6%), long philtrum (77.6%), dark circles under the eyes (70.6%) and narrow chest (67.2%), with large floppy ears and, in the classic description, microcephaly [5, 18].

Endocrine. Hypoparathyroidism is universal and is as a rule diagnosed in the first month (median age 29 days); tetany occurred in 53.3% and hypocalcaemic seizures in 64.2% [18]. Other endocrine abnormalities include hypothyroidism in 17.3% (primary in 15 patients, central in 6, and one case of Graves disease), hypoglycaemia in 27.8%, growth hormone deficiency in 14.3%, adrenal insufficiency in 3.2% and insulin-treated non-autoimmune diabetes in 1.6% [18]. Padidela and colleagues found hypoplasia of the adenohypophysis, infundibulum and corpus callosum in six children, with low IGF-1 in all, low growth hormone in 4/5, a subnormal cortisol response and signs of hypogonadotropic hypogonadism in the three boys [5].

Neurodevelopment. Developmental delay is universal (mild in 46.3%, moderate in 46.3%, severe in 7.4%), epilepsy not otherwise specified affects 26.2% and intellectual disability was recorded in 30.5% without formal psychometric assessment [18]. On MRI in 18 patients, pituitary hypoplasia (61.1%) and thin corpus callosum (77.8%) were frequent; basal ganglia calcifications appeared in 29% of a cohort of 24 [18, 34].

Airway, lung and infections. Craniofacial dysmorphism, the restrictive thorax and laryngeal abnormalities (retroflexed epiglottis, redundant supraglottic mucosa) make the airway difficult and predispose to sleep-disordered breathing, central hypoventilation and pulmonary hypertension [34]. Recurrent respiratory (63.7%) and bacterial (53.8%) infections are frequent; 35.6% of the registry patients were on antibiotic prophylaxis, and immunodeficiency was confirmed in 4 of 15 studied (T-cell, B-cell, NK and combined); immunological studies show raised IgA and IgE, a poor antipneumococcal antibody response, reduced B cells and an inverted CD4/CD8 ratio [7, 18, 34]. In an Iranian series of 19 patients, mean haemoglobin was 10.16 g/dL and leucocytes 13.37 × 10⁹/L, with microcytic anaemia, raised RDW and increased eosinophils, basophils and monocytes [77].

Digestive system and nutrition. Gastro-oesophageal reflux disease in 29.1% (fundoplication in 6.3%), nasogastric tube feeding in 24.6% and gastrostomy in 6.2%; in Jordan, chronic intestinal pseudo-obstruction affected 22.7% of 22 patients [18, 78].

Kidney. Nephrocalcinosis affected 62.1% of the 116 patients with ultrasound in the Gulf registry and 31.8% in the Jordanian series; one report describes a 12 mm calcium phosphate staghorn calculus at 11 years [18, 34, 78].

Eyes and teeth. Microphthalmia (45%), strabismus (42%), retinal vascular tortuosity (35%), corneal opacity (17%) and nanophthalmos; small, hypoplastic teeth (53.8%), caries (47.9%), delayed dentition (82% in the systematic review) and taurodontism [7, 18, 24].

Skeleton. Bone age is delayed in about 90%, and medullary stenosis appears in a minority (8.3% in one series; 15% in the systematic review), with patchy osteosclerosis in some pedigrees [6, 7, 34].

Mortality. In the Gulf registry, 25 of 124 patients (20.2%) had died, with a median age at death of 9.0 years; respiratory failure caused 84% of deaths and septic shock 24%; estimated median survival was 27.2 years and 62.4% survived to 18 years [18]. In the Jordanian series, 10 of 22 patients (45.5%) died, mainly from pneumonia and sepsis [78].

3.5. Neurological and muscular TBCE phenotypes

In PEAMO, the picture begins in childhood with progressive encephalopathy, distal amyotrophy due to axonal motor neuropathy and optic atrophy, without hypoparathyroidism; MRI shows progressive thinning of the corpus callosum and cerebro-cerebellar atrophy, and scoliosis and respiratory and digestive dysfunction accompany the course [27, 30]. In MRSG, myopathy with rigid spine and scoliosis and hypogonadotropic hypogonadism in men predominate, also without hypoparathyroidism [6, 64].

3.6. Progressive encephalopathy with amyotrophy and optic atrophy (PEAMO)

Sferra and colleagues described, in 2016, six patients (five boys and one girl) from four apparently unrelated families, all from the Naples metropolitan area (including Pozzuoli and Mergellina) and the island of Ischia, in Campania, one of them consanguineous [30]. Pregnancy and the neonatal period were normal, with birth weights between 2570 and 3490 g at 37–39 weeks; signs appeared between birth and 14 months, in the form of hypotonia and developmental delay or of spasticity and delay in the first year, and a regression followed with distal amyotrophy of all four limbs, foot drop, ataxia, spastic tetraparesis or paraparesis and optic atrophy [30, 31]. Between 6 and 20 years, one patient maintained sitting, one never acquired it and four lost it; two did not speak and four had dysarthria, severe in three; cognitive impairment was mild in one, moderate in three and severe in two [30]. Electrophysiological studies showed motor neuropathy in all, with fibrillation potentials limited to distal muscles, and muscle biopsy showed fibre-type grouping and denervated angular atrophic fibres [30, 31]. One patient had focal seizures at 12 years, refractory at 18; scoliosis occurred; no patient had a growth defect, dysmorphism, endocrine abnormalities, hypoparathyroidism or recurrent infections [30, 31].

Magnetic resonance imaging (MRI) showed, between 1 and 3 years, hypoplasia of the corpus callosum and cerebellar atrophy with prominent folia, and in the four patients assessed in the second decade, T2, FLAIR and T2* hypointensity in the globus pallidus, substantia nigra and red nucleus, due to iron deposition, in a pattern similar to that of neurodegeneration with brain iron accumulation (NBIA); in one family, MRI also showed brainstem atrophy and white matter hyperintensity [30]. The authors suggest that the iron pattern may be an age-dependent feature, appearing in the second decade [30]. Battini and colleagues described, in 2021, a girl from Southern Italy with early-onset regression, tetraparesis, signs of peripheral nervous system involvement and white matter changes, diagnosed by a hypomyelinating leukodystrophy gene panel [35].

Sartorelli and colleagues gathered, in 2026, 13 patients with a neurodegenerative phenotype from three centres (eight new and five already published) and a systematic review with 322 additional patients, for a total of 335 patients with TBCE variants, including monoallelic and biallelic variants; SSS accounted for 85% and the neurodegenerative phenotype for 5% [27]. The neurodegenerative spectrum ranges from spastic-ataxic tetraparesis with optic atrophy and distal axonal motor neuropathy, corresponding to PEAMO, to a milder complicated spastic paraparesis; MRI frequently shows progressive thinning of the corpus callosum, cerebro-cerebellar atrophy, white matter changes and possible iron accumulation in the deep grey nuclei, and scoliosis and respiratory and digestive dysfunction complete the multisystem picture [27]. The authors describe at least four phenotypes with genotype-phenotype correlation and their own geographical distribution [27]. The eight new patients, all homozygous for p.(Ile155Asn), were between 2.25 and 7 years old at last assessment [31].

Table sources: [27, 30, 31].

A case from Sferra illustrates the chronology of the disease: a boy born in 2007 to consanguineous parents from the Naples area, after a normal pregnancy and delivery (3360 g at 39 weeks), presented with hypotonia and developmental delay at around 4–5 months, followed by distal amyotrophy, ataxia and spasticity [30]. Muscle biopsy showed fibre-type grouping and angular atrophic fibres positive for non-specific esterase, and MRI at 2 and 3 years showed hypoplasia of the corpus callosum and cerebellar atrophy with prominent folia (figure 1 of the original paper) [30]. Trio exome sequencing identified homozygosity for c.464T>A p.(Ile155Asn), confirmed by Sanger sequencing and with family segregation, and the fibroblasts showed less TBCE and less polymerised α-tubulin; at 6 years, he could sit, spoke with dysarthria and had mild cognitive impairment [30]. MRI of the siblings in family 4 at 13 and 17 years documents the iron pattern in the pallidum, substantia nigra and red nucleus (figure 2 of the original paper) [30].

3.7. TBCD encephalopathy (PEBAT)

The disease begins, in most, in the first year of life, after a usually normal pregnancy and delivery. In Miyake's eight patients, onset was at birth (asphyxia and fractures, with polyhydramnios, in a Japanese family), in the first month (poverty of movement and hypotonia), at 5 months (hypotonia and regression) and at 9–11 months (seizures, in the Iraqi Jewish family); all had postnatal microcephaly and absent visual tracking, six postnatal growth retardation and seizures (one with West syndrome), five respiratory failure, four optic nerve atrophy and raised creatine kinase, and two tongue fasciculations; six became immobile, five were ventilated, and three died at 4, 4 and 19 years [32]. Of Flex's seven patients, all had spastic tetraplegia, six scoliosis and optic atrophy, five seizures and four microcephaly; four never walked and three never acquired head control or sitting, and those who walked lost walking due to progressive spasticity; there were subtle and variable dysmorphic features (sparse eyebrows, upslanting palpebral fissures, hypertelorism, micrognathia, widely spaced teeth) and, in most, swallowing difficulties and chronic constipation [8, 33]. Pode-Shakked described five patients with microcephaly, refractory epilepsy, optic disc pallor or atrophy and delayed myelination, and Ikeda two siblings with a picture of atypical spinal muscular atrophy followed by progressive brain atrophy [51, 52]. Al-Bakheet described nine patients from four Saudi families with neutropenia and, to a lesser degree, anaemia and thrombocytopenia, and Quitmann intermittent neutropenia in two siblings [37, 79].

Table sources: [19, 32, 33, 79].

In the Faroese cohort, collected over 28 years, all patients had normal weight and Apgar scores and normal early development; they were referred for developmental stagnation, truncal hypotonia, reduced lower limb activity, reduced attention, incipient spasticity or seizures, and progressed with regression, refractory epilepsy, aspiration and recurrent pneumonia; four had bilateral hip dislocation [19]. Optic atrophy was described in 14 of the 20 published patients with this information [19]. Grønborg was unable to separate an intrinsically faster progression from the effects of ascertainment bias in favour of long-surviving patients or from differences in supportive care, but noted that survival did not change over the 28 years [19].

MRI shows predominantly frontal cortical and global atrophy, loss of white matter volume, a thin or almost absent corpus callosum and, in late stages, cerebellar and brainstem atrophy, without cortical dysplasia or simplified gyral pattern [19, 32, 33]. The nature of the white matter abnormality differs between series: Flex and Pode-Shakked describe secondary hypomyelination and spectroscopy with low N-acetylaspartate, which favours primary neuronal injury, whereas in the Faroese patients myelin was appropriate for age on MRI and histology, despite the volume reduction [19, 33, 51]. Neuropathology showed a six-layered cortex, laminar necrosis, vacuolisation and neuronal loss, white matter gliosis, loss of neurons of the anterior horn of the spinal cord and of the brainstem motor nuclei, degeneration of the corticospinal tracts and muscle with a denervation pattern [19, 32].

The attenuated forms broaden the spectrum: sisters who acquired walking and had moderate intellectual disability at 16 and 17 years, a patient with spastic paraplegia and seizures only in childhood, three children with autism spectrum disorder and occasional seizures, and a woman who presented at 22 years with fatigue since childhood, distal weakness and amyotrophy and lower limb areflexia, with an intelligence quotient of 61, no epilepsy and a hypoplastic corpus callosum [32, 33, 71, 72].

Quitmann described two siblings, children of unrelated parents from a community of German immigrants in Russia, who illustrate the course and the diagnostic difficulties. The sister presented at 8 months with seizures initially associated with fever, progressive lower limb hypotonia from 6 months and secondary microcephaly; MRI at 8 months showed reduced supratentorial white matter and hypoplasia of the corpus callosum, followed by progressive atrophy with hydrocephalus ex vacuo; motor conduction was slowed and muscle biopsy showed denervation. The seizures, myoclonic and tonic, persisted on several antiseizure medications and ceased with a ketogenic diet; she had dysphagia, recurrent respiratory infections, intermittent neutropenia and premature thelarche, and died at 7 years of a respiratory infection. The brother developed normally until 3 months, had hypotonia at 6 months, febrile and then almost continuous seizures at 12 months, reduced by phenobarbital and, later, by a ketogenic diet with a 3:1 lipid ratio; he has received most of his nutrition by gastrostomy since 2.5 years and was 10 years old at the time of publication. The first exome, in 2013, gave no diagnosis; the second, in 2018, identified c.230A>G p.(His77Arg) and c.2048_2052dup p.(Glu685Ter) in TBCD, and review of the old data showed that the second variant had only three reads in the sister [37].

3.8. TBCB-related complicated spastic paraplegia (NEDBSPG)

Bratman Morag's ten patients, aged 3 to 43 years and from eight Ashkenazi Jewish families, had motor and language delay from infancy, with slightly late acquisition of walking and speech [9, 36]. Eight had autism spectrum disorder (two with Asperger syndrome), five attention deficit hyperactivity disorder and four anxiety; five of the eight formally assessed had mild intellectual disability, with intelligence quotients mostly between 60 and 69 [9]. The spastic paraplegia, age-dependent and slowly progressive, began between 9 and 12 years; the four patients over 25 years walked unaided and had no urinary symptoms, the upper limbs were not relevantly affected and no patient had seizures; one patient studied had sensorimotor polyneuropathy on electromyography [9]. MRI, performed in five, showed a thin corpus callosum in three, two of them with reduced white matter, and was normal in two [9]. Most had variable dysmorphic features or distal anomalies: frontal bossing, sloping forehead, widely spaced eyes, micrognathia, bulbous nose, high-arched palate, ptosis, strabismus, claw or hammer toes, long thin fingers, camptodactyly and pectus excavatum [9]. The data come from a single series assembled through genotype sharing, which limits estimation of the natural history [16].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

A second-trimester ultrasound showing growth restriction, limb shortening, a cloverleaf or poorly ossified skull, micrognathia with retrognathia, a small thorax and, sometimes, fractures or a bowed radius should lead to consideration of OCS, in addition to the more frequent lethal dysplasias; most of these signs are present at 20 weeks [1, 28, 46]. In one of the fetuses of Rosato and colleagues, the combination of micromelia and cloverleaf skull first led to the hypothesis of thanatophoric dysplasia and to a normal FGFR3 study [28]. In KCS2, short long bones may be detectable on prenatal ultrasound, but intrauterine growth restriction is uncommon; in SSS, severe symmetrical growth restriction is almost constant [1, 18, 43].

4.2. Neonatal period and infancy

The most common presentation of the whole class is symptomatic hypocalcaemia in the first days or weeks of life: seizures, tetany, irritability, apnoea or laryngospasm, with low calcium, raised phosphate and low or inappropriately normal PTH [1, 34]. Hypocalcaemia with hyperphosphataemia in a newborn should prompt simultaneous measurement of intact PTH, magnesium, blood glucose and electrolytes, because PTH measured during hypocalcaemia distinguishes true hypoparathyroidism from secondary hypocalcaemias [34]. The signs pointing to the TBCE family are: severe intrauterine growth restriction, microcephaly, deep-set eyes, beaked nose, thin upper lip, micrognathia, large ears, parental consanguinity or a sibling affected or who died in infancy, and Arab or Bedouin origin [18, 34]. The signs pointing to the FAM111A family are: normal birth weight, macrocrania with large fontanelles and widely separated sutures, a triangular or "elfin" face, midface hypoplasia, small hands and feet with dysplastic nails and normal development [1, 55].

4.3. Childhood and adulthood

KCS2 may be recognised in the investigation of severe proportionate short stature, especially when associated with a late-closing anterior fontanelle, high hypermetropia, dental anomalies and radiographs with medullary stenosis and thickened cortex; hypocalcaemia may appear later, as in a 7-year-old boy in whom it was detected after one year of growth hormone treatment [29, 43]. In adults, marked short stature with "idiopathic" hypoparathyroidism, cataracts, basal ganglia calcifications, nanophthalmos or chronic kidney disease without an evident cause justifies reviewing the long bone radiographs [1, 7]. In syndromic approaches, the Oxford Desk Reference includes KCS among the causes of a large anterior fontanelle (with short stature, cortical thickening, medullary stenosis, transient hypocalcaemia in infancy and normal intelligence, and a more severe recessive form due to TBCE with intrauterine growth restriction and congenital hypoparathyroidism) and among the dysplasias with increased bone density and gracile bones [80, 81]. Among inborn errors of metabolism, Saudubray's table of endocrine abnormalities lists KCS, due to FAM111A or TBCE, among the causes of hypoparathyroidism, alongside β-oxidation defects (LCHAD, trifunctional protein), respiratory chain diseases and STX16-related pseudohypoparathyroidism, which makes metabolic investigation part of the differential in an infant with hypocalcaemia [82]. The Second International Workshop guideline recommends considering genetic testing in non-surgical hypoparathyroidism when there is a family history, syndromic features or age under 40 years [83]. In a cohort of children with primary hypoparathyroidism, KCS accounted for one of 37 cases [55].

4.4. Emergency signs

Seizures, laryngospasm, apnoea, tetany and QT interval prolongation due to hypocalcaemia are emergencies; in SSS, infections, fever and dehydration precipitate hypocalcaemic crises, and the most frequent causes of hospital admission in a longitudinal cohort were hypocalcaemia (45%), fever (33%), seizures (25%), dehydration (13%) and hypoglycaemia (12%) [34]. In the newborn with OCS, respiratory distress due to pulmonary hypoplasia dominates the immediate prognosis [1]. There is no newborn screening for these diseases; in Israel, the TBCE founder allele is included in the national carrier screening programme [26, 84].

4.5. Neurodegenerative TBCE phenotype

PEAMO should be considered in an infant or young child with hypotonia and developmental delay progressing to motor regression, especially when associated with distal amyotrophy with foot drop, pyramidal signs, ataxia and optic atrophy, and when MRI shows a thin corpus callosum and cerebellar atrophy [27, 30, 31]. In the second decade, hypointensity of the pallidum and substantia nigra may lead to a diagnosis of NBIA, and the combination with distal motor neuronopathy is the element that points to TBCE [30]. Family origin in Campania strengthens the suspicion, and the absence of hypocalcaemia, dysmorphism and growth restriction separates PEAMO from SSS [30]. Warning signs are loss of safe swallowing, respiratory failure (in Sartorelli's eight patients, there was gastrostomy in five, non-invasive ventilation in four and invasive ventilation in two), progressive scoliosis and refractory seizures [27, 31].

4.6. TBCD and TBCB diseases

PEBAT should be considered in an infant with normal or slightly delayed early development who, in the first year, loses skills and develops axial hypotonia, spasticity, progressive microcephaly and epilepsy, especially with predominantly frontal cortical atrophy and a thin corpus callosum on MRI, without cortical malformation [8, 19]. The combination with lower motor neuron signs (tongue fasciculations, areflexia, denervation on electromyography), neutropenia or optic atrophy strengthens the suspicion, and Faroese or Cochin Jewish origin or a consanguineous family guides testing [19, 32, 70, 79]. Warning signs are respiratory failure, aspiration and recurrent pneumonia, refractory seizures and hip dislocation [19]. NEDBSPG should be considered in a child or adolescent of Ashkenazi Jewish origin with mild global delay, autism spectrum disorder and gait disturbance due to lower limb spasticity from 9–12 years [9].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

No consensus clinical diagnostic criteria have been published for the FAM111A disorders or for SSS/KCS1 [1, 18]. The diagnosis of a FAM111A disorder is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic variant identified by molecular testing; a variant of uncertain significance neither confirms nor excludes the diagnosis [1]. In the Gulf registry, patients without genetic testing were included on the basis of prenatal growth restriction, hypoparathyroidism, typical craniofacial dysmorphism and small hands and feet, which shows that, in populations with a founder allele, clinical diagnosis is still used [18].

5.2. Biochemical assessment

The combination of hypocalcaemia, hypomagnesaemia, low PTH and hyperphosphataemia is uncommon outside this class and has also been described in autosomal dominant hypocalcaemia due to CASR or GNA11 variants and in one case of Gitelman syndrome [7].

5.3. Imaging

The complete skeletal survey shows, in KCS2, medullary stenosis with thickened cortex, thin diaphyses, a calvaria without diploë and a large fontanelle; in OCS, a hypomineralised cloverleaf skull, gracile bones with flared metaphyses, thin ribs and fractures; and in SSS, delayed bone age and, sometimes, medullary stenosis or patchy osteosclerosis [34, 43, 46]. As medullary stenosis may not be evident in the neonatal period, repeating the study at 2 years was decisive in one published case [55]. GeneReviews recommends cranial CT for hydrocephalus, other malformations or craniosynostosis, and considering MRI for intracranial calcifications; renal ultrasound should form part of the initial assessment in SSS, because nephrocalcinosis may already be present, and of the assessment of older children and adults with KCS2 [1, 34]. In OCS, abdominal ultrasound assesses the spleen [1].

5.4. Genetic tests and their limits

For FAM111A, sequencing detects all known pathogenic variants, and deletion and duplication analysis has not to date identified any causal variant; the single gene may be used when the phenotype is distinctive, a skeletal dysplasia or hypoparathyroidism panel, or the exome or genome when the picture is non-specific [1]. Panels vary in content and sensitivity between laboratories [1]. For TBCE, in patients of Arab, Bedouin or North African origin, targeted testing for c.155_166del is the fastest route; in the others, gene sequencing or the exome [26, 62]. In practice, the diagnostic pathway often includes exclusion of the 22q11.2 deletion by MLPA or FISH and sequencing of genes for isolated hypoparathyroidism and hypomagnesaemia (CASR, GCM2, CLDN16, FXYD2, TRPM6, EGF) before the exome [7, 17].

The limits of the tests should be stated in the interpretation. A negative result on a panel does not exclude the diagnosis if the gene is not included or coverage is incomplete; FAM111A variants of uncertain significance are frequent in new families, such as p.Glu535Gly or the compound variants of the Turkish family; low-level parental mosaicism may not be detected in leucocytes; and the TBCE founder allele is an in-frame 12-nucleotide deletion that should be described with normalised notation [1, 7, 13, 17]. Truncating variants or deletions of the FAM111A gene found on panels do not have the support of the recurrent missense variants and call for caution, despite the isolated report of c.405delA [1, 58]. The report should state the gene, the transcript with version (NM_001312909.2 or NM_003193.5), the HGVS c. and p. notation, the zygosity, the ACMG/AMP classification and, in de novo or recessive cases, the result of parental testing [1, 13].

5.5. Algorithm

Algorithm sources: [1, 7, 26, 28, 34].

5.6. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal diagnosis by amniocentesis or chorionic villus sampling and preimplantation genetic testing are possible in both families [1]. In pregnancies without known risk with ultrasound signs of OCS, FAM111A sequencing or prenatal exome sequencing are appropriate; a British series of 52 pregnancies with rapid prenatal exome sequencing showed the impact of this test on management [1, 85]. In 2026, two Chinese fetuses with OCS diagnosed by trio exome sequencing, with de novo variants, were described [61].

5.7. Diagnosis of PEAMO

Assessment includes electromyography and nerve conduction studies, which show axonal motor neuropathy with distal fibrillation; brain MRI, with iron-sensitive sequences (T2* or susceptibility-weighted) from the second decade; ophthalmological examination with fundoscopy for optic atrophy; and confirmation of normal calcium, phosphorus and PTH, which excludes SSS [27, 30, 31]. Muscle biopsy, which shows denervation, is no longer needed when the molecular diagnosis is obtained [30].

The molecular diagnosis was made by trio exome sequencing, by targeted TBCE sequencing in monozygotic twins from the same region, by querying an exome database and by a hypomyelinating leukodystrophy panel; spastic paraplegia, distal motor neuropathy, NBIA and leukodystrophy panels only detect the disease if they include TBCE [30, 35]. In patients originating from Campania, targeted testing for c.464T>A is the fastest route, and finding a single allele requires a search for a second variant in trans, such as c.924del [30, 35]. The report should use the MANE transcript NM_003193.5 and normalised notation: the variant published as c.1076delC p.(Leu360Ter) corresponds to c.924del p.(Leu309Ter) [13, 63]. Copy number variations of TBCE have not been described in patients with PEAMO, and a negative result on a panel without TBCE does not exclude the disease [27, 30].

5.8. Diagnosis of the TBCD and TBCB diseases

There is no biochemical biomarker; assessment includes brain MRI, electroencephalography, electromyography and nerve conduction studies, which show motor neuronopathy or polyneuropathy, ophthalmological examination and full blood count, and serves to support the interpretation of the genetic result [15, 79]. Creatine kinase may be raised, and Miyake attributed the rise to asphyxia, fractures or seizures [32]. Hypoparathyroidism is not part of PEBAT, and calcium, phosphorus and PTH separate it from SSS [32].

The diagnosis is molecular, by exome or genome sequencing, or by epileptic encephalopathy, neurodegeneration, motor neuronopathy or spastic paraplegia panels, which only detect the disease if they include TBCD or TBCB [15, 16]. In patients of Faroese origin, targeted testing for NM_005993.5:c.3099C>G may precede the exome, and in those of Ashkenazi origin, testing for NM_001281.3:c.589T>A [19, 36]. The technical limits are documented: in Quitmann's case, the second variant was missed in the first exome because of insufficient coverage of the region and was only detected on reanalysis with a new capture five years later, which justifies repeating the analysis of negative exomes [37]. Multi-exon deletions require copy number variation analysis, and a single allele found in a patient with a compatible phenotype requires a search for them [37]. The interpretation of structural variants also has limits: in an Amish patient, a homozygous duplication of exons 8 to 13 of TBCD, initially classified as likely pathogenic, was revealed by long-read sequencing to be a complex duplication-inversion-duplication rearrangement that leaves the native gene intact, interpreted as benign, without the ACMG/ACGS criteria for copy number variants allowing it to be formally classified; the work is published as a preprint [86]. Ocampo-Chih described two children from Central America with the same homozygous variant of uncertain significance, whose interpretation relied on the phenotype and protein modelling [87]. The report should state the MANE transcript (NM_005993.5 for TBCD; NM_001281.3 for TBCB), the HGVS notation, the zygosity and the ACMG/AMP class, and parental testing confirms the trans phase of compound variants [13, 33].

6. Differential Diagnosis

6.1. Comparative table

Table sources: [1, 3–7, 20, 28, 34, 43, 46, 88, 89].

The causes of hypoparathyroidism that appear in this table as differentials — the 22q11.2 deletion, GATA3-related HDR syndrome, autosomal dominant hypocalcaemia due to gain of function of CASR and GNA11, the isolated forms due to GCM2 and PTH and hypocalcaemia due to TRPM6 hypomagnesaemia — belong to congenital and hereditary hypoparathyroidism, whose management brings together the diagnostic algorithm starting from hypocalcaemia with low or inappropriately normal parathyroid hormone, the biochemical targets of conventional therapy, the indications for parathyroid hormone replacement and the surveillance plan; Kenny-Caffey syndrome and Sanjad-Sakati dysplasia are the syndromic forms with bone dysplasia within that group.

6.2. Main differential diagnoses

The first differential is internal to the class. Distinguishing between the FAM111A family and the TBCE family changes the recurrence risk (50% or low de novo risk versus 25%) and carrier testing; the most discriminating features are intellectual disability (93% in KCS1 versus 21% in KCS2) and the bone phenotype (medullary stenosis in 96% in KCS2 versus 15% in KCS1), followed by intrauterine growth restriction (97% versus 31%), consanguinity (95% versus 6%), late closure of the fontanelle and relative macrocephaly, typical of KCS2 [7, 26]. The overlap is real: there are patients with KCS2 and microcephaly or intellectual disability, and patients with SSS and medullary stenosis [6, 7, 75].

The second differential is the 22q11.2 deletion, the most frequent syndromic cause of paediatric hypoparathyroidism. Sabry and colleagues described a consanguineous family with a KCS picture and an interstitial 22q11 deletion, and the bone dysplasia atlas records tubular stenosis with other manifestations of KCS in 22q11.2 haploinsufficiency, possibly secondary to fetal or infantile hypoparathyroidism [4, 43]. In the Manchester paediatric cohort, hypoparathyroidism resolved in 11 of 26 patients with the 22q11.2 deletion, above all when diagnosed in infancy, unlike the forms in this class [88].

The third differential is biochemical: in pseudohypoparathyroidism PTH is raised, and in hypocalcaemia due to hypomagnesaemia calcium normalises rapidly after magnesium replacement, unlike the persistent hypocalcaemia of SSS [34, 89]. In the prenatal period, OCS is confused with thanatophoric dysplasia, lethal osteogenesis imperfecta and fetal hypokinesias; the combination of a hypomineralised cloverleaf skull, gracile bones with abrupt metaphyseal flaring, medullary stenosis and splenic hypoplasia is what distinguishes OCS, and none of the other lethal dysplasias has cortical thickening with medullary stenosis [1, 46]. Hallermann-Streiff syndrome, considered by some authors to be related to OCS, has no splenic hypoplasia and is not lethal [28, 46]. The bone dysplasia atlas uses KCS and OCS as differentials of other entities: in 3M syndrome, KCS is distinguished by hypocalcaemia and the face; in microcephalic osteodysplastic primordial dwarfism types 1 and 3, the thin bones of KCS are associated with cortical thickening and hypocalcaemia, and those of OCS are straight, with abrupt metaphyseal flaring and hypoplastic distal phalanges; in sclerosteo-cerebellar syndrome, KCS has a narrow medullary cavity without sclerosis [90–92].

6.3. Differential diagnosis of PEAMO

Table sources: [6, 30, 31, 33, 36, 64].

The tubulin-folding cofactor diseases form a group: TBCD causes an early-onset encephalopathy in which, unlike TBCE, microtubule polymerisation is accelerated and stable microtubules increase, and TBCB, which acts together with TBCE in α/β heterodimer dynamics, causes a complicated spastic paraparesis with later onset [33, 36]. PEAMO shares with the tubulinopathies the neuronal vulnerability to microtubule disturbance, but without the malformations of cortical development that characterise them [30].

6.4. Differential diagnosis of PEBAT and NEDBSPG

Table sources: [8, 9, 19, 31, 33, 36, 52].

Flex compared PEBAT with the pontocerebellar hypoplasias and with aspartate-glutamate carrier 1 deficiency (SLC25A12), in which primary neuronal injury precedes secondary myelin loss, and with spastic paraplegia 4, in which microtubule hyperstability also causes axonal degeneration [33]. In the Faroe Islands, the SUCLA2 founder variant was excluded in all patients before identification of the TBCD variant, and the transient methylmalonic aciduria described in one of Quitmann's patients shows that this finding is not enough to separate the two diseases [19, 37]. Presentation with neonatal weakness and tongue fasciculations may suggest spinal muscular atrophy, and Ikeda described PEBAT as a cause of atypical spinal muscular atrophy followed by brain atrophy [32, 52]. In NEDBSPG, the combination of autism and global delay with late-onset paraplegia and a thin corpus callosum overlaps with the complicated spastic paraplegias, and Ashkenazi origin points towards targeted testing [9, 36].

7. Treatments and Risk Management Strategies

7.1. Principles and level of evidence

There is no treatment directed at the cause in either family, nor specific clinical guidelines: the FAM111A GeneReviews chapter brings together expert recommendations based on about 35 published patients, and for SSS there is a narrative review with expert opinion (2026) and a registry whose authors conclude that multidisciplinary guidelines are lacking [1, 18, 34]. Management of hypoparathyroidism relies on the general guidelines: the Second International Workshop (2022, GRADE methodology, 50 experts), the 2025 good practice recommendations that update it, the revised guideline of the European Society of Endocrinology (ESE, 2025) and the consensus of the German-speaking region (DACH, 2025), all focused on adults [65, 83, 93, 94]. There is no specific international consensus for children and adolescents with hypoparathyroidism; the paediatric doses used below come from Atiyah's review, from the INFARMED summaries of product characteristics (SmPC) and from the Food and Drug Administration (FDA) label, and are flagged as extrapolation where applicable [34, 95–98]. The team includes paediatric endocrinology, nephrology, orthopaedics, respiratory medicine and otorhinolaryngology (above all in OCS and SSS), ophthalmology, dentistry, immunology, neurology, nutrition, physiotherapy, occupational and speech therapy, and psychology [1, 34].

7.2. Hypocalcaemic crisis

A crisis (seizures, tetany, laryngospasm, apnoea, arrhythmia) is treated with intravenous calcium under electrocardiographic monitoring, simultaneous correction of magnesium and blood glucose and airway protection [34, 97]. In SSS, the airway is difficult (difficult mask ventilation and intubation, due to supraglottic anomalies and micrognathia) and so is venous access, so Atiyah's review recommends planning intraosseous access early, using ultrasound-guided puncture and considering early central access when peripheral attempts fail; fever, sepsis and dehydration precipitate crises and should be sought [34].

Ceftriaxone must not be mixed or administered with intravenous solutions containing calcium, and must not be used in newborns aged 28 days or less who are receiving intravenous calcium [97].

7.3. Chronic treatment of hypoparathyroidism

Targets. The adult guidelines recommend conventional therapy with calcium and active vitamin D metabolites as first line (weak recommendation, low-quality evidence), with corrected calcium in the lower half of the reference range, absence of symptoms, urinary calcium, phosphate and magnesium within reference values and 25-hydroxyvitamin D above 50 nmol/L [65, 83]. For SSS, Atiyah proposes total calcium of 8.0–8.5 mg/dL (2.0–2.1 mmol/L), phosphate of 4.5–5.5 mg/dL and a calcium × phosphorus product below 55 mg²/dL² [34]. GeneReviews calls, for the FAM111A family, for maintenance of normal calcium and phosphorus to reduce the risk of cataracts and intracerebral calcifications [1]. Native vitamin D does not replace calcitriol or alfacalcidol, because renal 1α-hydroxylation depends on PTH [26].

The divergence between the alfacalcidol starting doses in the SmPC (1 µg/day above 20 kg) and the usual maintenance dose in SSS (0.25–1 µg/day) is resolved by the consensus reference and by biochemical titration: the label serves as the comparison, and the effective dose is the lowest that keeps calcium at the low-normal target without hypercalciuria [34, 96]. Malabsorption, described occasionally in hypoparathyroidism, may require higher doses of calcitriol [95, 98].

7.4. Prevention of nephrocalcinosis and renal protection

Nephrocalcinosis is the main iatrogenic complication: without PTH, the distal tubule does not reabsorb calcium and any dose that normalises serum calcium increases calciuria [26]. In SSS it affected 62.1% of patients in the Gulf registry, and in a British paediatric cohort with hypoparathyroidism of various causes (80 patients, 754 patient-years) it affected 28.8%, associated with severe genotypes, early diagnosis, lower calcium, more time below target, a higher urinary calcium/creatinine ratio and a higher dose of active vitamin D per kilogram; the glomerular filtration rate was as a rule preserved and nephrocalcinosis regressed in three patients [18, 88]. Prevention rests on the low-normal target, the urinary calcium/creatinine ratio, periodic renal ultrasound and, when nephrocalcinosis is present, reduction of calcium and active vitamin D, hydration and a thiazide [34]. In KCS2, the chronic kidney disease described by Schigt and colleagues occurred without hypercalciuria or nephrocalcinosis in most, which led the authors to propose monitoring of renal function in all patients, including those without hypoparathyroidism [7].

7.5. PTH replacement therapy

The adult guidelines reserve PTH for patients not controlled with conventional therapy (persistent symptoms, hospital admissions, serum or urinary calcium outside the target, hyperphosphataemia, renal insufficiency, intolerance or poor quality of life); about 10% (5–20%) of adults are estimated to be in this situation [65, 83, 94]. A 2026 Italian Delphi consensus (20 experts, consensus on 39 of 41 statements) underlined the limitations of conventional therapy and of off-label use of teriparatide and the need for structured care pathways [99]. In the European Union, rhPTH(1-84) ceased to be produced in 2024, and palopegteriparatide (Yorvipath®), a sustained-release PTH(1-34) prodrug, is authorised only in adults [65, 100, 101]. In the PaTHway trial, 79% of adults treated with palopegteriparatide became independent of calcium and active vitamin D, with normalisation of mean 24-hour calciuria [65].

In children, teriparatide (rhPTH 1-34) has been used off-label in refractory cases. A meta-analysis of 18 studies and 94 patients aged 21 years or under showed serum calcium similar to that with conventional therapy (weighted mean difference -0.02; 95% CI -0.10 to 0.07), lower phosphate (-0.28; 95% CI -0.45 to -0.12), variable calciuria, growth and bone mineral density within normal limits, and concluded that conventional therapy remains first line [102]. In the paediatric series, subcutaneous teriparatide doses, given twice daily, ranged from 0.26 to 1.5 µg/kg/day (maximum 20 µg twice a day); calciuria fell, but nephrocalcinosis appeared or worsened in some patients, and continuous pump infusion was associated with episodes of hypo- and hypercalcaemia [57]. In 2026 the first use in KCS2 was published: a Serbian newborn with p.Ser541Pro, hypocalcaemia refractory to conventional therapy and central catheter-associated sepsis received teriparatide from day 58, 0.54 µg/kg/day in two doses (2.2 µg/day), with ethics committee approval, for 14 months; the calcium infusion was stopped on the third day because of hypercalcaemia, and at 2 years the patient maintained normal calcium and phosphorus on calcitriol 0.25 µg/day and magnesium oxide, with a urinary calcium/creatinine ratio ≤0.5 and no nephrocalcinosis [57]. In SSS, one infant received teriparatide 1–1.5 µg/kg/day for a few days [57]. These data are case reports and do not support routine use; the theoretical concern about the osteosarcoma observed in rats and open epiphyses mean that the FDA label for palopegteriparatide states that it is not approved in paediatrics [57, 101].

7.6. Regulatory table

7.7. Clinical trials and new developments

A search of ClinicalTrials.gov (1 November 2026) found no trials specific to KCS, OCS, SSS, FAM111A or TBCE [103]. The studies are heterogeneous, not comparable with one another and almost all outside this class of diseases; the paediatric meta-analysis brings together mainly small non-randomised series, and the adult data with palopegteriparatide do not apply directly to patients with syndromic congenital hypoparathyroidism [65, 102]. The developments of the last 12 months are observational or regulatory in nature: the international SSS registry with 135 patients (October 2026), the review of emergency care in SSS (July 2026), the first use of rhPTH in KCS2 (case report, March 2026), the review of 335 patients with TBCE variants (March 2026), the description of the MRSG muscular phenotype (2025), the start of the phase 3 trial in adolescents (April 2026) and the revision of the FDA label for palopegteriparatide (August 2026), which maintains the restriction to adults [18, 27, 34, 57, 64, 101, 103]. At the preclinical level, the study of the truncating variant c.405delA suggests a role for osteoclast necroptosis, without therapeutic translation [58].

7.8. Growth and growth hormone

GeneReviews records growth hormone deficiency in three patients with KCS2 and notes that the response to recombinant hormone has not been systematically assessed [1]. In an Australian girl with KCS2 and normal nocturnal secretion (peak 15 µg/L), growth hormone started at 3 years and 3 months at 4.9 mg/m²/week (0.2 mg/kg/week), increased to 7.24 mg/m²/week (0.33 mg/kg/week), raised growth velocity from 5 to 6.5 and 7.2 cm/year and height from -3.86 to -3.18 standard deviations at 5 years and 11 months; the authors considered the response limited [55]. In another patient, height went from -5.99 to -3.38 standard deviations at 12 years with growth hormone and IGF-1 [55]. In a 7-year-old Turkish boy treated for partial growth hormone deficiency, hypocalcaemia appeared after one year, which reinforces the need to monitor calcium during this treatment [29]. In SSS, seven patients in the Gulf registry started growth hormone and all stopped it, although Marsden described a good response in a patient with demonstrated deficiency [5, 18]. The short stature of KCS2 is not due to a primary disturbance of the somatotropic axis, and the decision to treat should be based on documented deficiency and realistic expectations [55].

7.9. Breathing, airway, infections and anaesthesia

Newborns with OCS who survive need intensive respiratory support and follow-up of restrictive lung disease by respiratory medicine [1]. In SSS, infection prevention includes airway clearance techniques, up-to-date vaccination against respiratory pathogens, early antibiotic therapy and, in 35.6% of the registry, antibiotic prophylaxis; immunological assessment (immunoglobulins, vaccine response, lymphocyte subsets) is justified in the presence of recurrent infections [18, 34]. Sleep-disordered breathing should be sought by polysomnography, and cardiovascular assessment includes the QT interval [26, 34]. Anaesthesia and sedation require planning for a difficult airway and control of calcium, magnesium and blood glucose before and after the procedure; adrenal insufficiency, present in 3.2% of patients with SSS, should be considered in the event of perioperative instability [18, 34].

7.10. Eyes, teeth, skeleton and development

Refractive errors and cataracts are treated in ophthalmology; nanophthalmos requires monitoring of intraocular pressure and uveal effusion, and one case of uveal effusion syndrome with serous detachment resolved with oral prednisone and acetazolamide, without surgery [1, 43, 74]. Dental assessment should start with eruption, preferably by 2–3 years, with caries prevention and prosthetic rehabilitation when needed [1, 73]. Scoliosis and torticollis are treated conservatively or surgically according to severity; in the two adults with KCS2 with severe torticollis and scoliosis, treatment was conservative [1]. Short stature benefits from environmental and occupational adaptations and occupational therapy [1]. In SSS, developmental delay requires scheduled physiotherapy and speech therapy, and feeding difficulties may justify caloric supplementation, a feeding tube or gastrostomy [18, 34].

7.11. Pregnancy, lactation and transition

In the pregnancy of a woman with hypoparathyroidism, calcitriol requirements may increase in the second half of gestation and decrease in the postpartum period and during lactation, which requires close monitoring of calcium [95]. Women with KCS2 can have children (maternal transmission is the best documented), and pregnancy should be followed jointly by endocrinology and obstetrics; the prenatal good practice guideline for skeletal dysplasias, built by Delphi consensus of 13 experts with 40 recommendations, applies to the pregnant woman with a dysplasia and to the affected fetus [1, 104]. When OCS is suspected in the fetus, referral to maternal-fetal medicine and discussion with the family about prognosis and resuscitation depend on the centre, and ultrasound indicators of lethality help the decision [1]. Transition to adult care should ensure continuity of renal, ophthalmological, dental and endocrine surveillance, assessment of fertility in men and reproductive counselling [1, 73].

7.12. Agents and situations to avoid

Avoid native vitamin D as a substitute for calcitriol or alfacalcidol; phenytoin and phenobarbital in chronic epilepsy; ceftriaxone with intravenous calcium in newborns; abrupt discontinuation of calcium and active vitamin D; overtreatment that takes calcium to the upper limit of normal; and, in patients with hypomagnesaemia, drugs that aggravate magnesium loss, such as proton pump inhibitors and diuretics, which Atiyah's review lists among the causes of hypomagnesaemic hypocalcaemia [26, 34, 95, 97].

7.13. Treatment of PEAMO

There is no targeted treatment, and management is multidisciplinary and supportive, focused on motor rehabilitation, nutritional support (gastrostomy in five of eight patients), ventilatory support (non-invasive ventilation in four and invasive in two), monitoring and correction of scoliosis (seven of eight patients) and treatment of seizures, present in three of eight patients and refractory in one of Sferra's patients [27, 30, 31]. Patients with PEAMO do not have hypoparathyroidism and do not need calcium or active vitamin D [30]. There are no trials of iron chelation in this disease, and iron deposition on MRI is not enough to extrapolate the treatments used in other forms of NBIA [27, 30].

From the gene therapy standpoint, PEAMO would be a candidate for a gene replacement strategy, because it results from partial loss of function of an intracellular protein in a recessive disease; the only preclinical evidence available is germline transgenic complementation of the pmn mouse, in which expression of normal Tbce from conception restored the phenotype, which demonstrates the causality of the gene, but does not test the administration of a vector after the onset of degeneration, nor the dose, route or safety in a patient [31]. The sources consulted describe no studies with viral vectors, phase 1 trials or efficacy and toxicity data in humans, and a search of ClinicalTrials.gov (1 November 2026) found no trials for TBCE or PEAMO [103].

7.14. Treatment of the TBCD and TBCB diseases

There is no targeted treatment or guideline for PEBAT or NEDBSPG, and the management described in the published series is supportive: antiseizure medications, respiratory support for progressive respiratory failure, nutritional support with gastrostomy when swallowing is no longer safe, physiotherapy for spasticity and contractures, surveillance of the hips and spine and anticipatory counselling about the course [15, 19, 87]. Epilepsy is frequently refractory: in the Faroese cohort it was treatment-resistant in all patients, and in Quitmann's siblings several combinations of antiseizure medications (sulthiame, oxcarbazepine, topiramate, ethosuximide, levetiracetam, phenobarbital and potassium bromide, the last stopped because of adverse effects) reduced seizures without eliminating them, while the ketogenic diet controlled seizures in the sister and reduced their frequency in the brother, with a 3:1 lipid ratio and ketonuria above 80 mg/dL [19, 37]. These data come from two patients, and the sources consulted do not allow a particular antiseizure medication to be recommended. In patients with neutropenia, the sources describe the finding without specific management [37, 79]. In NEDBSPG, the approach follows that of the hereditary spastic paraplegias and neurodevelopmental disorders, with physiotherapy, orthoses when needed and educational and behavioural intervention; the sources do not describe specific pharmacological treatments [9, 36].

From the gene therapy standpoint, both diseases are recessive with loss of function of intracellular proteins, which makes them theoretical candidates for gene replacement; the toxicity of TBCD overexpression, which depolymerises microtubules in cell culture and causes ectopic dendritic arborisation in Drosophila, requires control of the expression level [14, 33]. The preclinical evidence available is limited to models: expression of normal human TBCD partially corrected the axonal defects of tbcd-null Drosophila neurons, and correction of the biallelic missense variant by CRISPR/Cas9 and piggyBac transposon in a patient-derived induced pluripotent stem cell line restored the protein level and mitotic spindle organisation and reduced cell death, serving as an isogenic control for study and not as therapy [32, 105]. The sources consulted describe no studies with vectors, in treated mammals or in humans, and a search of ClinicalTrials.gov (1 November 2026) found no trials for TBCD, PEBAT or TBCB; the only record returned for "TBCD" refers to the abbreviation for Thiel-Behnke corneal dystrophy [103].

8. Reproductive Options and Family Counselling

8.1. FAM111A family

KCS2 and OCS are autosomal dominant [1]. In KCS2, most probands have a de novo variant, but there are families with vertical transmission: mother to son in the original description, mother to daughter with p.Arg569His, mother to a daughter and two sons (Majewski) and, since 2023, the first paternal transmission, in a Dutch family with four affected children [2, 7, 28, 42, 60]. Testing of the parents is recommended. If a parent is a carrier, the risk to each sibling is 50%; if the variant is not detected in the leucocytes of either parent, with confirmed parentage, the empirical risk to siblings is about 1%, because of theoretical germline mosaicism; if the parents are not tested but are clinically normal, the risk is low [1]. Each child of a person with KCS2 has a 50% probability of inheriting the variant [1]. Variable expressivity within families (for example, a maternal aunt with a typical craniofacial appearance who died of heart failure at 47 years, or siblings with different degrees of kidney disease) prevents prediction of a child's severity from the parent's phenotype [7]. One case of OCS in two siblings born to a mother with asymmetrical dwarfism suggested maternal somatic and germline mosaicism [3].

In OCS, all probands studied had de novo variants, with one possible exception: the consanguineous Turkish family with compound heterozygosity inherited from unaffected parents and two affected siblings, which raises the hypothesis of a rare recessive form [1, 17]. Siblings of a proband with a de novo variant have a risk of about 1%, and patients with OCS do not reproduce [1]. Thomas and colleagues and Korniszewski and colleagues described siblings with lethal gracile bone dysplasia without FAM111A testing, and it is not known whether they correspond to the same disease [3].

8.2. TBCE family

SSS/KCS1 and the allelic phenotypes are autosomal recessive: each sibling of a proband has a 25% risk of being affected, 50% of being a carrier and 25% of inheriting neither variant [5, 26]. First-degree consanguinity was present in 85.2% of the families in the Gulf registry and in 88.8% of the Jordanian families, and the carrier frequency of the founder allele is 1/49 among Negev Bedouins, where the variant is included in the Israeli national carrier screening programme for reproductive purposes [18, 26, 78, 84]. Atiyah recommends genetic counselling and screening in high-risk populations [34]. Mistaking the gene between FAM111A and TBCE changes the recurrence risk and carrier testing, which justifies molecular confirmation before counselling [26]. In PEAMO, the risk to each sibling is also 25%; the parents of a homozygous patient are carriers of p.(Ile155Asn), and those of a compound heterozygote each carry one of the alleles, which requires confirmation of phase by parental testing [30, 35]. In one of Sferra's four families there was consanguinity, and in the others homozygosity resulted from the regional founder effect; two sibling pairs (monozygotic twins in one family) were affected [30]. In relatives originating from Campania, carrier testing can be targeted at c.464T>A, but no carrier was found among 400 controls from the Naples area, which does not justify population screening [30].

8.3. Prenatal and preimplantation diagnosis and counselling of minors

Once the familial variant is known, prenatal diagnosis and preimplantation genetic testing are possible; the ideal time to discuss these options is before pregnancy, and GeneReviews recommends offering reproductive counselling to young adults with KCS2 [1]. Fetal ultrasound has limited value in excluding KCS2, because intrauterine growth restriction is uncommon, but it is sensitive in OCS from 20 weeks [1, 28]. Men with KCS2 may have subfertility and microorchidism, and fertility should be assessed at the transition to adulthood [2, 73].

8.4. TBCD and TBCB diseases

Both diseases are autosomal recessive, with a 25% risk for each sibling of a proband, 50% of being a carrier and 25% of inheriting neither variant; the parents of a compound heterozygous patient should be tested to confirm phase [8, 9, 33]. In the Faroe Islands, 8 of 306 controls were carriers of c.3099C>G (1/38; 2.6%), and identification of the variant allows targeted diagnosis and testing of at-risk couples [19]. In Cochin Jews, the c.1423G>A p.(Ala475Thr) variant was included in a screening programme of the Israeli Ministry of Health, developed with the community [70]. Among Ashkenazi Jews, the carrier frequency of NM_001281.3:c.589T>A estimated by Bratman Morag is 1.3% (192 in 14,804), which makes the variant a candidate for the carrier screening panels of that population; the decision to include it lies with the screening programmes, and the sources consulted do not describe its inclusion [9, 36]. Once the familial variants are known, the options of prenatal and preimplantation diagnosis and the principles of counselling minors described in 8.3 apply.

9. Special Considerations: Population Diversity and Epidemiology

9.1. FAM111A family

Prevalence is unknown; up to 2023, 35 patients had been published, and Orphanet classifies KCS and OCS as diseases with a prevalence below 1/1,000,000, with 65 and 30 cases or families recorded [1, 20, 22]. These figures count published cases and cannot be converted into a population rate. The patients come from diverse populations and there is no founder effect: Switzerland, Germany, Italy, Sweden, the United Kingdom, the Netherlands, Chile, India, Japan, Korea, China (Hong Kong), Australia, Canada, the United States, Turkey, Serbia and Brazil; in the systematic review, consanguinity was present in 6% of families with KCS2 [1, 7, 12, 17, 48, 55, 57, 60, 73]. In Brazil, a case of KCS2 with intellectual disability and microcephaly, interpreted as a phenotype overlapping with SSS, and a 10-year-old girl with maculopathy and intellectual disability have been published, both with de novo p.Arg569His [75, 76]. The sources consulted contain no data from Portugal.

9.2. TBCE family

SSS is concentrated in the Middle East and the Arabian Gulf: Saudi Arabia, Kuwait, Qatar, Oman, Jordan, Iran (Ahvaz) and Negev Bedouins in Israel, with cases in North Africa (Morocco) attributed to the Arab migration of the 7th century [5, 18, 24, 62, 77, 78]. The Negev Bedouins arrived in the region 400 to 500 years ago, coming from western Arabia, which explains the sharing of the haplotype with Saudi patients [5]. Birth prevalence has not been estimated; calculation from the carrier frequency (1/49) would violate the assumption of random mating in a population with high consanguinity [26]. In the review of 335 patients with TBCE variants, SSS accounted for 85% of cases and the neurodegenerative phenotype for 5%, with its own geographical distribution: PEAMO in Southern Italy and MRSG in Slavic populations (Russia, Poland, Ukraine), where c.100+1G>A is about 10 times more frequent than in gnomAD [6, 27, 64]. The Italian families with PEAMO came from the Naples metropolitan area (Pozzuoli, Mergellina) and the island of Ischia; no carrier of p.(Ile155Asn) was found among 400 unrelated individuals from the Naples area genotyped by ARMS-PCR (95% confidence interval of the frequency 0 to 0.0025), and in ExAC the variant appeared on a single allele out of 121,411, of unknown origin; these figures measure a regional sample and a reference database, not the prevalence of the disease [30]. A British patient born to parents from Qatar and a Belgian family with compound variants show that the disease also arises in Europe [5, 6].

9.3. Context of hypoparathyroidism

The prevalence of hypoparathyroidism of all causes, mainly post-surgical, has been estimated at between 6 and 34 per 100,000 people; the genetic forms in this class are a minimal fraction, but they are relevant causes of syndromic congenital hypoparathyroidism [55, 65, 88].

9.4. Special populations

Preterm newborns and patients with sepsis, dehydration or malabsorption are at greater risk of hypocalcaemic crisis; pregnancy alters active vitamin D requirements; and patients with SSS from consanguineous families may have concomitant recessive diseases that confound the phenotype [7, 34, 95].

9.5. Reference networks and patient associations

In Europe, ERN BOND (rare bone diseases) and Endo-ERN (rare endocrine diseases, including those of calcium and phosphate metabolism) are the relevant reference networks [38, 39]. In Portugal, ANDO Portugal (Associação Nacional de Displasias Ósseas) supports people with skeletal dysplasias [106]. For hypoparathyroidism, there are Hypopara UK and the HypoPARAthyroidism Association in the United States; GeneReviews also lists Short Statured People of Australia and the International Skeletal Dysplasia Registry of the University of California, Los Angeles (UCLA) [1, 107, 108]. For the neurological diseases of the cofactor family (PEAMO, PEBAT and NEDBSPG), the relevant network is ERN-RND (rare neurological diseases), and for refractory epilepsy EpiCARE [40, 41].

9.6. Epidemiology of the TBCD and TBCB diseases

PEBAT has a worldwide distribution, with patients published in Japan, Malaysia (Chinese family), Taiwan, Israel (Iraqi Jewish and Cochin Jewish families), Saudi Arabia, Italy, Germany (family of German-Russian origin) and in children from Central America seen in the United States [32, 37, 70, 71, 79, 87, 109]. Orphanet classifies the prevalence as <1/1,000,000 [11]. In the Faroe Islands, with about 49,000 inhabitants, the carrier frequency of c.3099C>G corresponds to a calculated incidence of 1/1444, and the eight patients identified between 1993 and 2016, with about 1000 births per year, to an observed incidence of 1/2875; the difference may reflect underdiagnosis, and in gnomAD the variant appears in 3 of 126,686 non-Finnish European alleles and is absent in other populations [19]. In Cochin Jews, the p.(Ala475Thr) variant was found in the homozygous state in unrelated families [50, 70].

NEDBSPG has been described only in Ashkenazi Jews. In this population, the allele frequency of c.589T>A was estimated at 0.65%, with 1.3% carriers; in gnomAD v4.1 the variant has a heterozygous frequency of 0.03%, with no homozygotes, and three of the families shared a haplotype, which indicates a founder effect [9]. These figures measure carrier frequencies and not the prevalence of the disease, which has not been estimated. The sources consulted include no patients from Portugal or Brazil for either disease, which does not demonstrate their absence.

10. Illustrative Clinical Case

Abraham and colleagues described a girl born at 39 weeks, by elective caesarean section for breech presentation, to non-consanguineous Italian parents, with a weight of 3.26 kg (0.1 standard deviation), length of 49 cm and head circumference of 36 cm (1.8 standard deviations) [55]. On the eighth day of life she had hypocalcaemic seizures: total calcium 1.15 mmol/L, ionised calcium 0.72 mmol/L, phosphate 4.07 mmol/L, magnesium 0.47 mmol/L, PTH below 0.3 pmol/L (reference 0.7–7), alkaline phosphatase 251 U/L and 25-hydroxyvitamin D 98 nmol/L, with normal blood glucose and renal function [55]. Normocalcaemia was achieved with a calcium gluconate infusion, and the patient subsequently maintained adequate calcium and phosphate with oral elemental calcium and calcitriol [55]. Examination showed macrocrania with persistent large fontanelles, an "elfin" face with midface hypoplasia, telecanthus, small palpebral fissures, a small upturned nose and a small chin, proportionate limb shortening with circular skin creases, small hands and feet with a single palmar crease and triangular, hypoplastic and dystrophic nails; the neonatal ophthalmological examination was normal (Figure 1 and Figure 2 of the paper: https://pmc.ncbi.nlm.nih.gov/articles/PMC5264330/figure/Fig1/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC5264330/figure/Fig2/) [55]. Development was normal, but growth was slow (65.5 cm at one year, -3.5 standard deviations) and the first tooth erupted at 16 months [55].

The 22q11.2 deletion and variants of PTH, CASR and GCMB were excluded. The neonatal radiograph was inconclusive; at 2 years, the medullary stenosis raised the hypothesis of KCS, and the skull radiograph showed deficient ossification of the calvaria, a patent metopic suture and widely separated sagittal sutures, while the tibial radiograph showed tubulated bones with reduced medulla and cortical thickening (Figure 6: https://pmc.ncbi.nlm.nih.gov/articles/PMC5264330/figure/Fig6/) [55]. At 4 years, sequencing identified a de novo FAM111A variant, c.1622C>A p.(Ser541Tyr) (normalised on NM_001312909.2), at a residue that the structural model places near the catalytic core of the protein [13, 55]. With normal nocturnal growth hormone secretion (peak 15 µg/L) and IGF-1 of 57 µg/L (-1.9 standard deviations), growth hormone was started at 3 years and 3 months, under the Australian criterion of short stature with slow growth, at 4.9 mg/m²/week; growth velocity went from 5 to 6.5 and then 7.2 cm/year with a maximum dose of 7.24 mg/m²/week, and at 5 years and 11 months the patient measured 98.9 cm (-3.18 standard deviations) and weighed 14 kg [55]. The authors emphasise the limited response and the need for registries of growth hormone outcomes in rare genetic diseases [55].

The case illustrates the typical chronology of KCS2: neonatal hypoparathyroidism without intrauterine growth restriction, macrocrania with large fontanelles, normal development, progressive short stature and medullary stenosis that only becomes evident after the first year [1, 55]. The use of growth hormone with normal secretion corresponds to a national funding criterion and not to a recommendation for the disease; GeneReviews considers that the response to this treatment has not been assessed [1, 55].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In KCS2, life expectancy is normal on current evidence, there are patients in the sixth decade and a man who lived to 77 years, and adult stature lies between 122 and 152 cm [1, 7, 43]. Long-term morbidity depends on control of mineral metabolism (intracranial calcifications, cataracts, nephrocalcinosis), on the chronic kidney disease described in some families, on the ocular complications of nanophthalmos, on tooth loss and on adult scoliosis [1, 7, 73, 74]. Sepsis caused the death of some patients with KCS2 [7].

In OCS, most die in the first hours or days from pulmonary hypoplasia, and the longest reported survival is 21 months [1, 46].

In SSS, mortality is high in childhood and adolescence: 20.2% deaths in the Gulf registry (median age at death 9.0 years), estimated median survival of 27.2 years (lower limit of the 95% CI 16.1 years) and 62.4% survival to 18 years; respiratory failure caused 84% of deaths and septic shock 24% [18]. In the Jordanian series, mortality was 45.5% [78]. In the registry, no variable studied (birth weight, seizures, nephrocalcinosis, reflux, antibiotic prophylaxis, genetic confirmation, hormonal deficiencies) was significantly associated with mortality [18]. PEAMO is progressive: in Sferra's series, four of the six patients lost sitting and one never acquired it, with patients alive at 15 and 20 years, and in Sartorelli's eight patients, assessed up to 7 years, there was progressive microcephaly in five, non-invasive ventilation in four and invasive ventilation in two; no survival data have been published [27, 30, 31]. MRSG has a more benign course [64].

In PEBAT, prognosis depends on the allele: in the Faroese cohort, all patients died between 10 and 56 months (median 24 months), mainly from respiratory complications, whereas in the 24 non-Faroese patients reviewed by Grønborg survival was longer, and in Miyake's series three of eight died at 4, 4 and 19 years, six became immobile and two sisters with p.(Pro937Arg) were walking at 16 and 17 years [19, 32]. The attenuated forms reach adulthood with walking, such as the distal motor neuronopathy diagnosed at 22 years [71]. In NEDBSPG, progression is slow, and the four patients over 25 years (up to 43 years) maintained independent walking and urinary continence [9].

11.2. Surveillance

The intervals in the table match those in section 7: quarterly biochemistry until stable and six-monthly thereafter in the FAM111A family, fortnightly during stabilisation and quarterly thereafter in SSS, and renal ultrasound annually (FAM111A) or six-monthly (SSS) [1, 34]. In PEAMO, calcium biochemistry is needed only at diagnosis, to exclude hypoparathyroidism, and the sources do not define intervals for neurological, respiratory and orthopaedic surveillance [27, 30]. In PEBAT and NEDBSPG, too, the sources do not define surveillance intervals, and the frequency of visits depends on the clinical course [9, 19].

12. Summary and Final Considerations

The Kenny-Caffey class brings together two distinct genetic families that converge on congenital primary hypoparathyroidism and a defect of tubular bone modelling. The dominant FAM111A family ranges from KCS2, in which a child of normal weight develops neonatal hypocalcaemia, proportionate short stature, relative macrocephaly, a large fontanelle, hypermetropia due to nanophthalmos, dental anomalies and medullary stenosis with thickened cortex, while usually maintaining normal intelligence and life expectancy, to OCS, in which a fetus with a hypomineralised cloverleaf skull, gracile bones, fractures and splenic hypoplasia as a rule dies from pulmonary hypoplasia. The variants are missense variants or in-frame single amino acid deletions in the protease domain, probably with gain of function, and do not allow severity to be predicted. The recessive TBCE family, with an Arab-Bedouin founder allele, produces SSS, which includes the former KCS1: severe prenatal and postnatal growth restriction, microcephaly, dysmorphism, developmental delay, pituitary deficiencies, infections and high respiratory and septic mortality; hypomorphic alleles of the same gene cause neurodegenerative and muscular forms without hypoparathyroidism. The distinction between the two families, guided by the features of intellectual disability, intrauterine growth restriction, consanguinity and bone phenotype and confirmed by molecular testing, determines recurrence risk and counselling. Treatment is that of hypoparathyroidism: intravenous calcium in crises, oral calcium, active vitamin D and magnesium for maintenance, with calcium targets at the lower limit of normal and monitoring of calciuria and the kidney to avoid nephrocalcinosis; replacement PTH is authorised only in adults, and its paediatric use, including the first case of KCS2, is off-label and reserved for refractory situations. Chronic kidney disease in KCS2, the airway and infection risks in SSS and ophthalmological and dental surveillance complete the long-term follow-up. A hypomorphic allele from Southern Italy, p.(Ile155Asn), preserves some TBCE and produces, instead of SSS, PEAMO: a neurodegenerative encephalopathy of early childhood with distal amyotrophy, spasticity, ataxia, optic atrophy, thin corpus callosum and, in the second decade, iron deposition in the basal ganglia, without hypoparathyroidism and without targeted treatment [27, 30].

The other cofactors of the same complex cause neurological diseases without hypoparathyroidism: biallelic TBCD variants cause PEBAT, an encephalopathy with regression in the first year, refractory epilepsy, motor neuronopathy and brain atrophy without cortical malformation, with hyperstable microtubules and severity dependent on residual function, which in the Faroe Islands is due to a founder variant with a median survival of 24 months; homozygosity for TBCB NM_001281.3:c.589T>A causes, in Ashkenazi Jews, a neurodevelopmental disorder with autism and spastic paraplegia with onset at the end of the first decade and slow progression. In both, treatment is supportive, and molecular diagnosis guides counselling and carrier screening in founder populations.

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