Hallermann-Streiff Syndrome

Oculo-mandibulo-facial dyscephaly with hypotrichosis (François dyscephalic syndrome), including the severe lethal Dennis-Fairhurst-Moore form

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1 Historical overview

Hallermann-Streiff syndrome (HSS) is a malformation syndrome recognisable by the association of abnormalities of the skull and face, eye, teeth, hair and skin with proportionate short stature. The first probable report dates from 1893 and was published in the Annales de Dermatologie et de Syphiligraphie under the title of a variety of congenital alopecia, "sutural alopecia", that is, absence of hair over the lines of the cranial sutures; the case was incomplete and the author's name is spelt Audry or Aubry depending on the source [3, 4]. In 1948, Hallermann published in the Klinische Monatsblätter für Augenheilkunde patients with a "bird face" and congenital cataract, and in 1950 Streiff independently described in Ophthalmologica the "bird-headed" mandibulofacial dysmorphism with ocular abnormalities; the three cases of these two authors established the entity [1, 3]. In 1958, Jules François reviewed the published cases and added hypotrichosis, skin atrophy, dental anomalies and short stature, defining the syndrome by seven features: dyscephaly with bird face, dental anomalies, proportionate dwarfism, hypotrichosis, skin atrophy, microphthalmia and congenital cataract [1, 4, 11]. François' article distinguished the new syndrome from progeria and from mandibulofacial dysostosis, but, in the absence of any genetic test, the original series probably included patients with different conditions [4].

The following decades accumulated case reports and reviews. Steele and Bass collected 50 cases in 1970 and emphasised the absence of the mandibular angle and the hypoplasia of the clavicles and ribs; Warburg argued in 1971 that the diagnosis is doubtful without cataract or microphthalmia [1]. In 1991, a thematic issue of the American Journal of Medical Genetics published Cohen's review, the radiological review by Christian and colleagues and reports on respiratory obstruction, tracheomalacia, hypopituitarism and overlap with oculodentodigital dysplasia (ODDD), consolidating the notion that upper airway complications are the main cause of severe morbidity and early death [12, 16–20]. Smith's textbook recorded about 150 published cases; in 2018, Schmidt and Wollnik described HSS as one of the few syndromes with a highly recognisable phenotype that remain without a molecular explanation, and the 2026 reviews count about 200 patients [3, 4, 21].

1.2 Milestones in molecular research

The search for a gene followed three lines. The first started from the resemblance to ODDD: in 2004, a homozygous GJA1 variant was described in a patient with an HSS/ODDD overlap phenotype, but the same study found no GJA1 variants in a patient with full HSS, and the patient with the variant was later reclassified as recessive ODDD [22, 23]. The second started from the resemblance to the progeroid syndromes: in 2011, sequencing of LMNA, ZMPSTE24 and ICMT in eight patients showed no relationship with the laminopathies [24]. The third used exome sequencing: in 2021, a de novo variant in CHD6 in a patient with HSS prompted an extensive functional study in induced pluripotent stem cells, but no other patients with variants in this gene have emerged [4, 7]. The review by Cavender, Atzinger and Slavotinek, published in February 2026, concludes that the aetiology remains unknown in almost all cases and proposes clinical criteria and a framework for multisystem assessment [4].

1.3 Nomenclature

OMIM uses the prefix "%" for entry 234100, which indicates a confirmed or suspected Mendelian phenotype whose molecular basis is unknown [1]. The eponym "François syndrome" is discouraged, because it is confused with another François syndrome (OMIM 221800) [1]. Orphanet maintains two entities: ORPHA:2108 for the usual form and ORPHA:2109 for the severe form, also called Dennis-Fairhurst-Moore syndrome [2, 5]. The expression "bird face", used in the original descriptions, is tending to be replaced by "characteristic facial gestalt"; Schmidt and Wollnik consider it inappropriate and recommend abandoning it [4, 21].

1.4 Definition of the entities covered

HSS is defined clinically by the association of congenital cataract and/or microphthalmia with the characteristic facial appearance (a thin, small, pointed nose that becomes "beaked" with age, with micrognathia or retrognathia), accompanied by at least two of four additional features: proportionate short stature, hypotrichosis or sparse fine hair, skin atrophy and dental anomalies [4]. The severe form corresponds to the sibship described by Dennis, Fairhurst and Moore in 1995, with thin long bones and intrauterine fractures, undermineralised skull, HSS face and cataracts, lethal in the neonatal or fetal period; it is not known whether it is the severe end of HSS or a distinct condition [4, 6]. The differential diagnosis with disorders of known gene (oculodentodigital dysplasia, Wiedemann-Rautenstrauch syndrome, FAM111A-related gracile bone dysplasia, progeroid laminopathies) is an integral part of the definition, because several patients published as HSS correspond to these entities [4, 23, 25].

2. Molecular Genetics and Pathophysiology

2.1 A syndrome without an established gene

HSS still has no confirmed causal gene. The group of Schmidt and Wollnik, in Göttingen, assembled over about ten years a cohort of patients with classic HSS and applied to it successively karyotyping, array-based comparative genomic hybridisation (array-CGH), singleton and trio exome sequencing, with DNA from different tissues to detect mosaicism, and singleton and trio genome sequencing, without identifying a common gene [21]. Sequencing of GJA1 in more than 20 patients with classic HSS identified no likely causal variants, and the exome revealed no pathogenic variants in genes for overlapping conditions, namely LMNA and ZMPSTE24 (Hutchinson-Gilford progeria and mandibuloacral dysplasia), POLR3A (Wiedemann-Rautenstrauch syndrome), SLC25A24 (progeroid gerodermia), CEP152 (Seckel syndrome) and TCOF1 (Treacher Collins mandibulofacial dysostosis), or in genes of the DNA damage response, telomere maintenance or genomic instability; trio analysis also found no causal uniparental disomies or variants in imprinted genes [4, 21]. The authors presented these results in a review, as a personal communication, without methods or the exact number of patients per technique, which limits their evaluation [21]. In the review of 24 patients published between 2003 and 2025, three had a normal karyotype and only two had exome sequencing, both without a diagnosis; the case of Guerin and colleagues combined an exome with analysis of 82 premature ageing genes and 1832 developmental disorder genes, also negative [4, 9]. HSS is considered probably genetic because of the high proportion of bilateral congenital cataracts and the absence of any suspected environmental cause [4]. The predominance of sporadic cases is compatible with de novo germline variants or with mosaicism, and genetic heterogeneity, epigenetic and gene-regulatory mechanisms and gene-environment interactions are considered possible [4]. Schmidt and Wollnik consider that the hypothesis of de novo dominant variants remains the best fit for the classic cases and attribute the absence of results to a combination of extensive genetic heterogeneity, variants in regulatory elements, small structural changes (for example, inversions affecting regulatory regions), uniparental disomy or variants in imprinted genes and somatic or revertant mosaicism in blood cells, without excluding more complex modes of inheritance or prenatal exposures; they propose trio genome sequencing with short and long reads, transcriptome profiling (RNA-seq), DNA from several tissues and larger cohorts, and accept that, once the cause is identified, genotype-phenotype correlations may emerge within the clinical spectrum [21]. An additional explanation is the heterogeneity of the clinical definition itself: the early series and many recent reports include patients with other syndromes, a phenomenon of "phenotypic drift" that the authors compare to that of Dubowitz syndrome [4].

2.2 Inheritance pattern: conflicting data

OMIM classifies inheritance as "isolated cases" and records that all cases have been sporadic [1]. The published family data point in opposite directions and are recorded together, because none has been confirmed molecularly [1, 4].

The 2026 review notes that, in the families with a dominant pattern, not all members had the classic facial gestalt, that several women with HSS had children without transmission and that increased parental consanguinity alternatively supports recessive inheritance in some cases [4]. Schmidt and Wollnik's statement that there are no formal reports of monozygotic twins diverges from OMIM, which records concordant monozygotic pairs in François' compilation and concordant and discordant pairs in Cohen's review; the difference probably results from the restriction of the 2018 review to classic cases with facial photographs, and the concordant monozygotic twin girls of Sims and colleagues were published later [1, 21, 29]. Smith's textbook states that no affected male has reproduced; this statement is contradicted by Guyard's man with an affected daughter, by the man with a healthy child in David's series and by the father in Epée's family [1, 3, 15, 28].

2.3 Candidate genes and unconfirmed associations

The variants below were described in patients with a clinical diagnosis of HSS. Human Genome Variation Society (HGVS) nomenclature was normalised in VariantValidator on the MANE Select reference transcript (Matched Annotation from NCBI and EMBL-EBI), on the GRCh38 assembly [30].

None of these variants has been replicated in another patient with classic HSS, so a negative result for these genes does not affect the clinical diagnosis and a positive result in GJA1, ZMPSTE24 or LMNA as a rule shifts the diagnosis to the known disorder of that gene [4].

2.4 CHD6: cellular model of a candidate variant

The work of Kargapolova and colleagues (2021) is the most extensive functional study of HSS. Exome sequencing of the patient and parents, on blood and saliva DNA, identified a single plausible de novo variant, the substitution of isoleucine by methionine at residue 1600 of CHD6, located in the second SANT/SLIDE domain (CHDCT2 domain), at a position conserved across species and also present in the SLIDE domain of CHD1 [7]. The authors reprogrammed the patient's fibroblasts into induced pluripotent stem cells (iPSCs) and created, by CRISPR-Cas9 editing, isogenic lines with the variant in the heterozygous state (as in the patient) or with the mutant allele only, differentiating them into neural crest cells and cardiomyocytes [7]. The mutant protein bound more chromatin sites than the normal one, without losing the ability to bind or remodel nucleosomes in vitro, but showed lower thermal stability and failed to recruit the BAF/PBAF complexes to the promoters of autophagy and stress-response genes; this resulted in impaired autophagic flux, accumulation of DNA damage and markers of cellular senescence (less H3K27me3 heterochromatin, HP1α foci, increased beta-galactosidase) [7]. Overexpression of the mutant protein in the neural tube of chick embryos caused, in two thirds of the embryos, severe facial malformations, absence of the first branchial arch or fusion of the first and second arches, an enlarged forebrain and reduced mesenchyme, as well as delayed ventricular development and cardiac septal abnormalities [7]. The authors interpret HSS as a neurocristopathy with features of premature ageing [7]. The limitations are clear: a single patient, with no published clinical description, and no additional CHD6 variant in patients with HSS since 2021 [4]. The association of CHD6 with HSS places this syndrome within the group of CHD gene-related disorders.

2.5 Relationship with GJA1 and oculodentodigital dysplasia

ODDD, caused by heterozygous GJA1 variants (connexin 43, 6q22.31), shares with HSS the narrow nose, microphthalmia with microcornea, dental anomalies and hypotrichosis; Meyer-Schwickerath noted this overlap with François dyscephalic syndrome as early as 1957 [33]. Spranger's bone dysplasia book states that GJA1 variants also cause HSS [34]. This statement is not supported: the OMIM phenotype map of GJA1 includes dominant and recessive ODDD, recessive craniometaphyseal dysplasia, erythrokeratodermia variabilis et progressiva 3, palmoplantar keratoderma with congenital alopecia and syndactyly type III, but not HSS; the "Hallermann-Streiff" patient with a homozygous variant was reinterpreted as recessive ODDD; and the association appears only in UniProt annotations, without a ClinGen or GenCC classification [22, 23, 35]. Schmidt and Wollnik record as consensus that the phenotype associated with recessive variants in the C-terminal region of GJA1 is not typical HSS [21]. GJA1 sequencing is justified in patients with syndactyly of the fourth and fifth fingers or other features of ODDD [4]. ODDD is included in the differential diagnosis.

2.6 Pathophysiology of the manifestations

In the absence of a molecular mechanism, pathophysiology is described at organ level. The upper airway is narrow because of the combination of small nostrils, midface hypoplasia, micrognathia with glossoptosis (posterior displacement of the tongue), microstomia and, in some patients, narrow choanae, tracheomalacia or laryngomalacia; chronic obstruction may progress to hypoventilation, pulmonary hypertension and cor pulmonale [1, 9, 17, 18]. The cranial changes result from deficient ossification of the calvaria and sutures, with wormian bones and persistent fontanelles, and the appendicular skeleton shows thin, gracile long bones with poor corticomedullary demarcation, which explains fractures in some patients [3, 12, 36]. The eye is small (microphthalmia, with an axial length of 12 to 18 mm in a series of four children) and the opaque lens may resorb spontaneously, with risk of uveitis, glaucoma, uveal effusions, exudative detachments and corneal opacities [29, 37–39]. Skin atrophy of the nose and sutural areas, hypotrichosis and telangiectasias bring the syndrome close to the group of disorders with ageing features, and this resemblance guided the search for laminopathies, so far negative [2, 21, 24]. Schmidt and Wollnik include HSS among the segmental accelerated ageing phenotypes, which reproduce features of physiological ageing in one or a few tissues: in addition to the pointed nose, fine hair and hypotrichosis, there are thin bones with progressively reduced mineralisation, recurrent infections and loss of subcutaneous fat; one patient with an initial diagnosis of HSS had an LMNA variant and mandibuloacral dysplasia [21]. Chromosomal and genomic instability has been described in one patient, but systematic chromosome breakage studies in two patients were normal, and in fibroblasts from several patients exposed to stress-inducing agents the DNA damage response, measured for example by phosphorylated histone H2AX (γH2AX), showed mild changes in some patients, but not in all [21, 24].

2.7 Genotype-phenotype correlations, penetrance and modifiers

Without a causal gene there are no genotype-phenotype correlations, penetrance estimates or known modifiers. Expressivity is variable: there are adults diagnosed in the seventh decade with subtle signs and infants with fatal respiratory obstruction [10, 17, 40]. There are no defined allelic disorders.

3. Clinical Spectrum and Manifestations by System

3.1 Data sources and frequency of the cardinal features

There are no prospective cohorts. The data come from small series and reviews of case reports, with publication bias in favour of severe or unusual presentations [4, 40]. The largest single-centre clinical series included 15 patients in a plastic and reconstructive surgery department in the USA (mean age 32 years; 7 males and 8 females) [15]. The review by Cavender and colleagues included 24 patients published between 2003 and 2025 (10 male and 14 female), after excluding those with features suggestive of another diagnosis; the systematic review by Abbas and colleagues (PRISMA, PROSPERO registration CRD420251248477, search up to 30 November 2025) included 32 cases from 15 studies published between 1991 and 2024, from newborns to adults aged 77 years, from Europe, Asia, Africa and the Americas [4, 40].

Sources for the table: [3, 4, 40]. The differences between columns reflect different inclusion criteria, periods and quality of description, and none of the series allows population frequencies to be estimated [4, 40].

3.2 Growth and endocrine aspects

One third of patients are born preterm, with low birth weight, or both, and two thirds have postnatal growth deficiency; stature is proportionate and mean final height is 152 cm in women and 155 to 157 cm in men, as a rule 2 to 5 standard deviations below the mean [1, 3, 21]. In the 2026 review, height ranged from −4.4 to −1.5 standard deviations, 14 of 24 patients had stature below the 5th centile or "growth delay" and 5 of 24 had low weight; birth weight and length were as a rule normal [4]. There are patients without short stature, such as a 26-year-old woman with the rest of the phenotype, and adults with more marked deficiency (143 cm and 38 kg at 68 years), who raise the possibility of another diagnosis [1, 4, 10]. Growth hormone deficiency is an occasional anomaly; Pivnick and colleagues described a 35-month-old boy with ketotic hypoglycaemia, microgenitalia and short stature who had hypothalamic hypothyroidism, adrenocorticotrophic hormone (ACTH) deficiency, gonadotrophin-releasing hormone deficiency and complete growth hormone deficiency [3, 19]. Hypogenitalism and cryptorchidism in males and micropenis have been described [3, 4]. Endocrine abnormalities are rare: in addition to hypopituitarism, hypothyroidism and, in one patient, hypoparathyroidism with humoral immunodeficiency have been described [21].

3.3 Skull and face

The skull is brachycephalic, with frontal and parietal bossing, a thin calvaria and delayed ossification of the sutures, and the large calvaria contrasts with the small facial skeleton; head circumference is as a rule normal or at the lower limit of normal [21]; scaphocephaly, microcephaly, platybasia and a shallow sella turcica are occasional [1, 3]. The face combines malar hypoplasia, micrognathia with hypoplasia of the mandibular rami and anterior displacement of the temporomandibular joint, an obtuse or right gonial angle and, sometimes, absence of the mandibular condyles [3, 12]. The nose is thin, small and pointed, with cartilage hypoplasia, and becomes "parrot-beaked" with age; the palate is narrow and high, the mouth small and the lips thin [1, 3]. There is a tendency to nasal septal deviation; the mandible may have a central cleft or dimple and a double chin; temporomandibular joint anomalies are common (aplasia or hypoplasia of the condyles, anterior displacement of the condyles and articular disc, obtuse mandibular angle, retrognathia); the paranasal sinuses are small, and maxillary hypoplasia with malocclusion is frequent and open bite occasional [21]. The ears are often low-set but of normal shape, and the absence of ear anomalies was one of François' five negative signs [21]. In the 2026 series, a small nose or small nostrils were present in 18 of 24 patients (75%), micrognathia in 15 (63%), retrognathia in 12 (50%), frontal bossing in 9 (38%), microstomia in 7 (29%), a high anterior hairline in 7 (29%), a high or narrow palate in 5 (21%) and minor ear anomalies in 3 (13%) [4]. In Caen, craniofacial deformities were recorded in 98 to 99% of cases [41].

3.4 Eye

The ocular defect is the main cause of disability and often culminates in blindness despite surgery [3]. Microphthalmia is as a rule bilateral and accompanied by microcornea (horizontal corneal diameter of 5.5 to 10.5 mm and axial length of 12 to 18 mm in four Indian children) [3, 37]. The cataract is total or partial, often membranous or formed by liquefied milky-white lens masses, and may resorb spontaneously, which is detected by ultrasound biomicroscopy (UBM) when the opacity prevents conventional examination [3, 37, 38]. Nystagmus and strabismus are frequent; blue sclerae, downslanting palpebral fissures, colobomas of the iris, choroid and optic disc, persistent pupillary membrane, chorioretinal pigmentary changes, retinal folds, entropion and ptosis occur in some patients [1, 3, 4]. In the synthesis by Schmidt and Wollnik, limited to classic cases, congenital cataract, microphthalmia, sparse eyelashes and eyebrows, nystagmus, strabismus, blue sclerae and fundus anomalies are common; conjunctival and corneal defects, downslanting palpebral fissures, ocular hypertension, iris atrophy and coloboma, vitreous degeneration, eyelid anomalies, persistent pupillary membrane, enophthalmos, hypotelorism, epicanthus and hypoplasia of the lacrimal puncta are occasional; and disc and choroidal colobomas, ptosis, epibulbar tumour, aphakia and retinal detachment are rare [21]. Complications include glaucoma (severe in 3 of 6 Belgian patients operated on for cataract), anterior uveitis, uveal effusions, retinal detachments, exudative in some cases, choroidal neovascular membrane and corneal opacities: five of six Belgian patients had the same pattern of ill-defined bilateral stromal opacities, seen at around 5 years of age and stable over 10 years of follow-up [29, 39, 42, 43]. Pigmentary retinal dystrophy with an abnormal electroretinogram and macular folds, with posterior segment features close to nanophthalmos, Brown-McLean syndrome (peripheral corneal oedema after surgery) and descemetocele with corneal perforation have also been described [4, 29, 44].

3.5 Teeth and oral cavity

Dental anomalies include natal or neonatal teeth (7 of 24 patients, 29%), selective agenesis up to partial anodontia, supernumerary teeth, retained deciduous teeth, enamel hypoplasia, microdontia, short roots, malocclusion and crowding, with a predisposition to severe caries [1–4]. In the North American series of 15 patients, findings ranged from small or missing teeth to complete anodontia [15]. A Moroccan child with an overlap phenotype and a homozygous GJA1 variant had "ghost"-like teeth due to enamel and dentine defects [31].

3.6 Skin and hair

Hypotrichosis affects the scalp, eyebrows and eyelashes, with fine, light hair; skin atrophy predominates on the nose and over the sutures, with visible veins, and telangiectasias and xerosis may be present [1–3]. Alopecia is most marked in the frontal and occipital regions, especially along the suture lines; Golomb and Porter described a hair shaft anomaly with an absent or malformed cuticle, and axillary and pubic hair may be sparse or absent [21]. In a 10-year-old child followed in Caen, the nasal atrophy had ulceration scars caused by pressure from spectacles [40].

3.7 Airway and respiratory system

The narrow upper airway is the most important potentially fatal complication [3, 16]. In the series of 15 patients, 11 had significant intermittent respiratory difficulty (early feeding difficulty, recurrent upper respiratory tract infections, sleep apnoea and respiratory arrest), three required tracheostomy and one child died of postoperative respiratory compromise [15]. In the 2026 review, 7 of 24 patients (29%) had recurrent respiratory infections, pneumonia or airway disease, three had obstructive sleep apnoea (OSA), one of them requiring mechanical ventilation, and one had respiratory distress at birth; in the systematic review, the airway was involved in more than half of the cases [4, 40]. Robinow described an infant with nasal obstruction from birth, aspiration pneumonia, progressive cor pulmonale and death at 11 months, and Salbert and colleagues a boy with tracheomalacia, chronic respiratory failure and biventricular heart failure who died at 6 months [17, 18, 40]. Severe feeding difficulties and pneumonia caused the early death of several infants, and postoperative respiratory difficulty appears to be frequent [21]. OSA may appear in the first months or only in adulthood: a 53-year-old Dutch woman had an apnoea-hypopnoea index (AHI) of 77.7 events per hour [9, 45]. In an 18-year-old Brazilian girl with lower-limb lymphoedema, lifelong nasal obstruction was attributed to facial lymphatic oedema [46].

3.8 Skeleton

Radiology shows a large, poorly ossified skull, wormian bones, midface hypoplasia with a prominent nasal bone, thin, gracile long bones with metaphyseal widening and poor corticomedullary demarcation, neonatal bowing of the radius and ulna, thin ribs of normal length, small vertebral bodies (platyspondyly in three of five patients), fewer sternal ossification centres, gracile metacarpals and delayed bone age [3, 12]. Scoliosis, lordosis, winged scapulae, pectus excavatum, joint hyperextensibility and spina bifida are occasional [1, 3]. The 2026 review identified a subgroup with blue sclerae, natal and fragile teeth, very thin tubular bones with fractures of the radius (spontaneous in one case), hip dysplasia, limb asymmetry, large fontanelles, redundant skin and severe short stature with low insulin-like growth factor 1 (IGF-1), hypothyroidism, heart disease, polymicrogyria and choanal atresia; the authors do not know whether this group is distinct [4]. A 12-year-old Mexican boy with a previous femoral fracture sustained a periprosthetic fracture after a fall from standing height, with a very thin femoral diaphysis [36].

3.9 Neurodevelopment and behaviour

Most patients have normal intelligence, but motor and intellectual deficits, sometimes severe, have been described; intellectual disability is reported in 15% [1, 3]. In the 2026 series, 8 of 24 had neurocognitive delay, which improved in two, three had motor delay (walking after 16 months) and two hypotonia; none had brain malformations, seizures, cerebral palsy or regression [4]. In the series of 15 patients, three had mild and three severe intellectual disability [40]. François included the absence or minimal degree of intellectual disability among the five negative signs of the syndrome [21]. Hyperactivity, psychosis, choreoathetosis and generalised tonic-clonic seizures were reported in old reports, and severe visual impairment contributes to delayed milestones [3, 9, 21]. Spaepen and colleagues suggested that marked short stature may indicate a higher risk of intellectual disability [20]. More recently, a 32-year-old man with psychosis was published, without it being known whether this is part of the syndrome [47].

3.10 Other systems

Congenital heart defects are rare (ventricular and atrial septal defects, patent ductus arteriosus, pulmonary stenosis and tetralogy of Fallot) [1, 4, 9, 21]. Sensorineural deafness and bilateral dehiscence of the posterior semicircular canal have been described [3, 48]. Submucous cleft palate, velopharyngeal insufficiency, gastro-oesophageal reflux with aspiration and need for gastrostomy, renal and hepatic anomalies, immunodeficiency and haematopoietic abnormalities occur in isolated cases [3, 4]. Hypospadias, clitoral enlargement, breast asymmetry or atrophy, hemihypertrophy, bilateral inguinal hernias, choanal atresia and muscle hypotrophy, of uncertain relationship with the syndrome, have also been described and, in isolated cases, agenesis of the corpus callosum, hydrocephalus and a small cerebellum, whereas none of the 24 patients in the 2026 review had brain malformations [4, 21].

3.11 Severe and lethal form

In the sibship of Dennis and colleagues, a boy died in the neonatal period and a female fetus died at 29 weeks; both had thin long bones with fractures, an undermineralised skull and an HSS face, and the boy had bilateral cataracts [6]. FAM111A-related gracile bone dysplasia is the main alternative diagnosis for this picture [13, 49].

3.12 Adults and late diagnosis

HSS may go unnoticed until adulthood when there are no marked aesthetic, visual or respiratory problems: a 68-year-old Japanese woman was diagnosed after surgeons noticed blue sclerae during cataract surgery, and the Cameroonian family of Epée had their first ophthalmology consultation at 77, 39 and 19 years of age, with heights of 1.58, 1.59 and 1.60 m [10, 28]. Smith's textbook mentions spontaneous pregnancy in affected women [3].

4. Clinical Recognition and Warning Signs

4.1 When to suspect

In the newborn and infant, suspicion arises in the presence of bilateral congenital cataract or microphthalmia associated with a small pointed nose, micrognathia, a brachycephalic skull with bossing and a soft calvaria, hypotrichosis of the eyebrows and eyelashes, atrophy of the skin of the nose and natal teeth [2–4]. HSS should be recognised in the first year of life; when the picture becomes apparent later, with loss of subcutaneous tissue, progressive alopecia or vascular changes, the progeroid syndromes become more likely [4]. In the paediatric cataract clinic, the association of bilateral cataract with microcephaly indicates a syndromic cause: in a London centre, among 85 infants with bilateral cataract diagnosed before 1 year of age (1997–2001), five had microcephaly, three with early-onset Cockayne syndrome, one with Micro syndrome and one with HSS, and the authors recommend measuring head circumference in every child with congenital cataract [50]. In adults, corneal opacities, short axial length with high hypermetropia, a shallow anterior chamber and blue sclerae, associated with a thin beaked nose, a receding chin and proportionate short stature, may lead to a late diagnosis [10].

4.2 Negative signs pointing to another diagnosis

Syndactyly of the fourth and fifth fingers, camptodactyly or other limb anomalies suggest ODDD; complex ocular anomalies (early exudative detachments, descemetocele, extensive colobomas) and additional malformations suggest another syndrome; ear anomalies and abnormal palpebral fissures suggest mandibulofacial dysostosis; muscle atrophy, chronic arthritis and early atherosclerosis suggest a progeroid condition; and severe intellectual disability is unusual in HSS [4]. In ODDD, the tubular bones are broad, whereas in HSS they are thin, and a thin calvaria with wormian bones is characteristic of HSS [34].

4.3 Warning and emergency signs

The emergency signs are respiratory. Snoring, breathing pauses, feeding difficulty with choking or aspiration, abnormal cry, stridor, fixed wheeze, chronic brassy cough, recurrent respiratory infections and daytime hypersomnolence require airway assessment and a sleep study, because they may reflect severe OSA, tracheomalacia or glossoptosis, with risk of hypoxaemia, cor pulmonale and death [1, 9, 17, 18]. Normal overnight oximetry does not exclude OSA: in the case of Guerin and colleagues, two normal oximetries (day 4 and 5 months) preceded polygraphy at 8 months with an obstructive AHI of 25 per hour [9]. Any anaesthesia is a risk situation, because mask ventilation and intubation may fail and the difficulty increases with age [14, 51]. In the eye, pain, photophobia, red eye or corneal clouding suggest glaucoma, uveitis or perforation, and sudden loss of vision suggests retinal detachment [29, 39, 42].

4.4 Newborn screening and prenatal diagnosis

There is no newborn screening. Prenatal ultrasound has no specific signs described for the usual form; in the lethal form, thin long bones with fractures and cranial undermineralisation are detectable, but overlap with skeletal dysplasias of known gene [6, 49].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Clinical criteria

There are no consensus-validated criteria. François' seven features remain the historical reference, and the facial gestalt was considered mandatory by Schmidt and Wollnik, for whom HSS should not be diagnosed without the typical craniofacial changes as long as the genetic cause is not known [4, 11, 21]. François' five negative signs included the absence of ear anomalies and the absence or minimal degree of intellectual disability [21]. Warburg considered the diagnosis doubtful in the absence of cataract or microphthalmia [1]. The 2026 review proposed operational criteria that all 24 patients reviewed would meet [4]:

Source for the table: [4]. These criteria result from a retrospective review of reports, have not been tested prospectively and have no known sensitivity or specificity [4].

5.2 Ancillary investigations

The initial evaluation includes a complete ophthalmological examination with biometry and, if the cataract prevents observation, ultrasound biomicroscopy and B-scan ultrasound to assess the lens, anterior chamber and retina before planning surgery; UBM may detect spontaneous lens resorption and avoid unnecessary anaesthesia [4, 37, 38]. A skeletal survey in the newborn shows the radiological pattern described (poorly ossified calvaria, wormian bones, obtuse gonial angle, gracile long bones with metaphyseal widening, thin ribs, fewer sternal centres) and helps confirm the diagnosis [12]. Airway assessment includes ear, nose and throat (ENT) review with endoscopy of the choanae, pharynx and larynx, respiratory polygraphy or polysomnography in the first months and tracheobronchoscopy if there are signs of tracheomalacia [4, 9]. Computed tomography (CT) or magnetic resonance imaging (MRI) defines the facial bony configuration for surgical planning, and high-resolution CT of the temporal bones is indicated if there is sensorineural deafness [4, 48]. Echocardiography and electrocardiography are justified before anaesthesia if heart disease is suspected or known [14]. Endocrine evaluation (somatotrophic axis, thyroid, cortisol, gonadotrophins) is justified in marked short stature, hypoglycaemia or microgenitalia [4, 19].

5.3 Role of genetic testing

There is no confirmatory test. The role of genetic testing is to exclude diagnoses with a known gene and to contribute to the discovery of the cause [4]. Exome or genome sequencing, preferably as a trio, covers GJA1 (ODDD), LMNA and ZMPSTE24 (progeria and mandibuloacral dysplasia), POLR3A (Wiedemann-Rautenstrauch), FAM111A (gracile bone dysplasia and Kenny-Caffey), TCOF1 and the other mandibulofacial dysostosis genes, CEP152 and primordial dwarfism genes, and the genes for Cockayne syndromes and syndromic congenital cataract [4, 9, 50]. Chromosomal microarray excludes copy-number variants and may reveal uniparental isodisomy, as in the patient with a mosaic ZMPSTE24 variant [25, 29]. When testing genes with pseudogenes or homologous regions, such as GJA1, the laboratory must ensure the specificity of the analysis [35].

5.4 Test limitations

A negative exome does not exclude a genetic cause: the exome does not reliably detect deep intronic variants, balanced structural rearrangements, expansions, epigenetic changes or low-level mosaicism in non-blood tissues, and the predominance of sporadic cases makes mosaicism a hypothesis to consider [4]. The patient with the CHD6 variant was studied on blood and saliva DNA, a useful approach when mosaicism is suspected [7]. A result with a variant of uncertain significance (VUS) in a candidate gene without an established association, such as CHD6, does not confirm the diagnosis; family segregation and confirmation of de novo origin are the indicated steps [4, 7].

5.5 Report content

The report of a genetic test in a patient with suspected HSS should state the type of test and coverage, the differential diagnosis genes analysed and, for each variant, the gene, the transcript with version (MANE Select), the HGVS c. and p. nomenclature, zygosity, origin when known and class according to the criteria of the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP). A negative result should state explicitly that it does not exclude HSS, whose diagnosis remains clinical [4].

5.6 Diagnostic algorithm

The proposed pathway is sequential. In an infant with congenital cataract and/or microphthalmia and a suggestive facial gestalt, at least two supporting features are confirmed and negative signs are sought; this is followed by ophthalmological examination with UBM, skeletal survey, airway assessment with polygraphy and dental examination; then microarray and exome or genome sequencing, ideally as a trio, with analysis targeted at the differential diagnoses; if testing identifies an alternative diagnosis, the patient falls outside the scope of HSS; if negative, the clinical diagnosis is maintained, with periodic reanalysis of the genomic data and consideration of genome sequencing or a mosaicism study [4, 9, 12].

5.7 Prenatal and preimplantation diagnosis

Without a causal gene there is no molecular prenatal diagnosis or preimplantation genetic diagnosis. If testing identifies a cause in a differential diagnosis, that cause then guides reproductive diagnosis. The anomaly scan may detect the lethal form and some differential dysplasias, without specificity [6, 49].

6. Differential Diagnosis

6.1 Comparative table

6.2 Oculodentodigital dysplasia

ODDD is the most frequent differential; it was the reason for excluding three of the patients published as HSS in the 2026 review, all with syndactyly (a 5-year-old Brazilian girl born to consanguineous parents, a 3-year-old girl with syndactyly of the fourth and fifth fingers and a 23-year-old woman with complete fusion of the same fingers), without GJA1 testing [4]. Spaepen and colleagues described in 1991 a child with the HSS face, without ocular abnormalities, with cleft palate and complete syndactyly of the fourth and fifth fingers, whom they considered an overlap of the two syndromes [20]. In the series of 54 genotyped families with ODDD, the characteristic facies was present in 92%, ocular abnormalities in 68%, dental abnormalities in 70% and digital abnormalities in 80% of families; neurological disease (30%) and conductive deafness (26%) also help to distinguish them [33, 55]. Radiology distinguishes them well: broad tubular bones in ODDD and thin ones in HSS [34]. The digital anomalies specific to ODDD (syndactyly of the fourth and fifth fingers, hypoplastic phalanges) are the main clinical distinguishing element [21].

6.3 Progeroid syndromes

HSS shares with the progeroid syndromes hypotrichosis, skin atrophy with visible veins and the pointed nose. Wiedemann-Rautenstrauch syndrome has a facies that may be confused with HSS, but it is progressive, with lipoatrophy, prominent veins and wide fontanelles, and leads to early death [52, 53]. The progeroid syndromes that are dysmorphic at birth (Wiedemann-Rautenstrauch, HSS, De Barsy, progeroid Ehlers-Danlos) are distinguished from classic progeria, which is normal at birth, by their own features and by molecular analysis [54]. The 4-year-old girl published as "possible HSS" who had ZMPSTE24 deficiency due to mosaic uniparental isodisomy illustrates the risk of labelling a laminopathy without cataract as HSS [25].

6.4 Gracile bone dysplasias

Osteocraniostenosis (FAM111A-related gracile bone dysplasia) resembles HSS and was once considered related; Elliott and colleagues noted radiological and histological similarities, but splenic hypoplasia is not part of HSS and the face is different [13, 49]. The lethal form of HSS and the skeletal subgroup with fractures described in 2026 should be tested for FAM111A [4, 6]. The primordial dwarfisms and 3M syndrome have thin bones, but not with the metaphyseal widening or digital anomalies of osteocraniostenosis [49].

6.5 Other causes of cataract and microphthalmia

In bilateral congenital cataract with microcephaly, early-onset Cockayne syndrome was the most frequent cause in a London series, ahead of Micro syndrome and HSS [50]. Nance-Horan syndrome, the microphthalmia-anophthalmia-coloboma syndromes and hereditary congenital cataracts enter the differential when the face is not characteristic [53].

7. Treatments and Risk Management Strategies

7.1 Principles and sources of recommendations

There is no causal treatment and no published clinical guideline for HSS [4, 14]. The available recommendations are the Orphananesthesia anaesthetic recommendations (last modified in October 2019), the assessment framework proposed by Cavender and colleagues in 2026, the recommendations of authors of reports and series (David and colleagues, Guerin and colleagues, Abbas and colleagues) and, for each complication, the general standards of the corresponding specialty, applied as in other diseases [4, 9, 14, 15, 40]. The initial priority is the complications that threaten life and development (airway and vision); aesthetic correction as a rule waits until the end of growth [15]. Follow-up is multidisciplinary: paediatrics or genetics as coordinator, paediatric ophthalmology, ENT, paediatric respiratory and sleep medicine, anaesthesiology, dentistry and orthodontics, maxillofacial surgery or a craniofacial team, endocrinology, dermatology and, when necessary, immunology or infectious diseases [4, 40].

7.2 Airway and obstructive sleep apnoea

ENT assessment at diagnosis and a sleep study in the first months, repeated throughout childhood, are the recommendations common to the sources; Guerin and colleagues prefer respiratory polygraphy (nasal flow, thoracic and abdominal movements, heart rate and transcutaneous oximetry) or polysomnography to oximetry alone, which may underestimate OSA [1, 4, 9]. Adenotonsillectomy is the first step when there is obstructive adenotonsillar hypertrophy, followed by repeat polygraphy or polysomnography, because in craniofacial malformations OSA frequently persists after surgery [9]. When severe OSA persists, three options are discussed in a multidisciplinary team. Non-invasive ventilation (NIV), by continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP), is effective in other craniofacial malformations and was successful in an infant with HSS; the difficulties are the choice of interface in a face with midface hypoplasia, the risk of aspiration with reflux, tolerance of high pressures and the effect of the mask on facial growth, which requires maxillofacial surveillance and polygraphy on NIV at least once a year [9]. Tracheostomy resolves the obstruction and was the option in most published cases (three of 15 in the North American series), at the cost of effects on oral feeding, speech and socialisation and of complications (infection, stenosis, granulomas, accidental decannulation or tube obstruction) [9, 15]. Maxillofacial advancement surgery is effective in OSA, but midface advancement requires mature ossification and is as a rule postponed until late adolescence or adulthood [9]. In a 53-year-old woman with an AHI of 77.7, orthodontic and surgical treatment with mandibular advancement reduced the AHI to 1 [45]. Tracheomalacia should be sought by tracheobronchoscopy in the presence of early inspiratory and expiratory noise, fixed wheeze, recurrent infections or chronic brassy cough, and is treated as outside HSS [9, 18]. Recurrent or severe respiratory infections justify referral to immunology or infectious diseases and to respiratory medicine [4]. In a Brazilian adolescent with lymphoedema, cervical and facial lymphatic drainage relieved nasal obstruction for months; this is an isolated report [46].

7.3 Anaesthesia and the perioperative period

The usual operations (ophthalmological, ENT, dental, maxillofacial and orthopaedic) are performed mainly in childhood, and both general and regional anaesthesia are feasible, with technical difficulties in both [14]. Orphananesthesia recommends preoperative airway assessment with imaging and ENT consultation, exclusion of active bronchopulmonary infection and echocardiography and electrocardiography if there is heart disease [14]. Airway difficulty appears to increase with age, and there are reports of difficulty with all modalities: bag-mask ventilation, direct and indirect laryngoscopy (videolaryngoscopy) and nasal intubation, and intubation of adults with HSS has been the subject of dedicated reports [14, 51, 56]. Videolaryngoscopy under induction with spontaneous ventilation has been successful, as has intubation with the Airtraq laryngoscope in an infant and with the aid of a bougie in an adult [14, 40, 57]. In the most severe cases primary tracheostomy should be considered, and a "cannot intubate, cannot ventilate" situation should be prevented by planning [14]. Regional anaesthesia may preserve spontaneous ventilation; joint hyperextensibility, fragility and scoliosis require care in positioning; antiseizure medications are continued perioperatively; and the postoperative period may be complicated by obstruction and apnoea, justifying prolonged saturation monitoring [14]. Day-case anaesthesia is possible if the surgery does not involve the airway and there is sufficient monitoring in recovery [14]. Skin fragility also complicates eyelid surgery [44]. In the series of 15 patients, one child died of postoperative respiratory compromise [15].

7.4 Eye

Ophthalmological examination is performed at diagnosis, and abnormalities are treated as in other conditions, with referral to a retina specialist when there are retinal findings [4]. Cataract surgery should be early to preserve vision and prevent amblyopia, but it is technically difficult because of microcornea, microphthalmia and membranous cataract [15, 37, 40]. In a series of four children, three underwent lens extraction and two strabismus surgery; they were left mostly aphakic and best-corrected visual acuity went from "fixes and follows light" to a postoperative median of 20/380, with one retinal detachment [37]. In a Swiss infant, bilateral lensectomy with posterior capsulorhexis and anterior vitrectomy was followed by correction with rigid gas-permeable contact lenses and visual follow-up for 4.5 years [40]. Preoperative UBM may show spontaneous lens resorption and avoid unnecessary surgery [38]. Glaucoma, frequent after cataract surgery (three of six Belgian patients), may require medical treatment and cyclodestructive procedures: in the monozygotic twins, topical timolol 0.25%, prednisolone 1% and atropine 1% preceded bilateral extraction with near-total capsulectomy, which normalised the pressure without timolol; the glaucoma recurred and was treated with endocyclophotocoagulation; in a Chinese adult, cyclocryotherapy controlled glaucoma refractory to medical therapy [29, 39, 58]. The twins received oral prednisolone 1 mg/kg/day for one week after surgery; recurrent exudative detachments did not respond to oral prednisolone, and a descemetocele with perforation required penetrating keratoplasty, with final acuity of 20/130 to 20/260 at 4–5 years [29]. In a 7-year-old boy, an exudative detachment due to a choroidal neovascular membrane resolved with intravitreal bevacizumab 1.25 mg, an off-label use [42]. In the Japanese adult, cataract surgery with goniosynechialysis and chelation of corneal calcification with ethylenediaminetetraacetic acid (EDTA) improved acuity and stabilised the pressure without medication [10]. Protection of the atrophic nasal skin from spectacle pressure should be considered, because pressure ulceration has been described [40].

7.5 Teeth, jaws and face

Dental and orthodontic assessment should include clinical examination and radiographs (bitewing, individual periapical and orthopantomography) for hypodontia, short roots and other anomalies, with emphasis on prevention and rigorous oral hygiene, because there is a predisposition to severe early caries; severe dental agenesis may justify referral to a feeding specialist, and the facial bony configuration is studied by CT or MRI with a craniofacial team [4]. Natal teeth and extractions of abscessed teeth, removable prostheses in childhood and behavioural management feature in the reports [31, 40]. In a patient followed for 20 years in Strasbourg, early genioplasty improved facial growth, dental implants placed before the end of growth provided orthodontic anchorage and complementary orthognathic surgery completed occlusion and aesthetics [59]. Rhinoplasty, facial augmentation and mandibular surgery have been performed successfully after growth [15]. Nasal lipofilling (autologous fat grafting) improved the colour and texture of the atrophic nasal skin in two patients in Caen [41]. A history of antiresorptive medication did not prevent tooth movement or cause osteonecrosis in an adult patient treated with orthodontics and surgery [45].

7.6 Growth and endocrinology

Height and weight are monitored regularly, with surveillance for asymmetry and scoliosis, and short stature justifies an endocrinology consultation; the efficacy of growth hormone in HSS is unknown [4]. When there is demonstrated growth hormone deficiency or hypopituitarism, as in the patient of Pivnick and colleagues, replacement follows the standards for that deficiency [19]. A Swiss infant received growth hormone, with no dose described in the available abstract [40]. There is no published somatropin dose for HSS; the label dose for paediatric growth hormone deficiency is used, which constitutes extrapolation: 0.16 to 0.24 mg/kg/week in 6 or 7 subcutaneous (SC) injections in the US Food and Drug Administration (FDA) label for Genotropin® and 0.025 to 0.035 mg/kg/day (or 0.7 to 1.0 mg/m²/day) in the summary of product characteristics (SmPC) for Omnitrope® approved by the European Medicines Agency (EMA) [60, 61]. In HSS, the most relevant warnings are respiratory: the US label contraindicates somatropin in children with Prader-Willi syndrome with upper airway obstruction or sleep apnoea, because of reported sudden deaths, and recommends assessing the airway before starting; the European SmPC contraindicates somatropin in acute respiratory failure and acute critical illness and warns of slipped capital femoral epiphysis, benign intracranial hypertension and worsening of scoliosis [60, 61]. By analogy, a child with HSS and OSA should have the airway assessed and treated before and during treatment [9, 60]. Treatment is stopped once the epiphyses have fused [60].

7.7 Skin, hair, orthopaedics, hearing and neurodevelopment

Hypotrichosis and sparse hair justify dermatological assessment [4]. The fragility of the thin long bones requires individual orthopaedic planning: in a 12-year-old boy with a periprosthetic femoral fracture, open reduction and internal fixation with a low-profile plate was used, with a good outcome at 6 months [36]. Scoliosis is monitored clinically [4]. In sensorineural deafness, high-resolution CT of the temporal bones is performed, and a cochlear implant may be considered according to the usual criteria [48]. Severe visual impairment requires early visual stimulation and developmental intervention; in the case of Guerin and colleagues, psychomotor milestones improved after OSA was controlled [9]. Feeding difficulties, reflux and aspiration may require gastrostomy, with or without fundoplication [4, 9].

7.8 Mental health

In a 32-year-old man with HSS and psychosis, risperidone resolved the psychosis and suicidal ideation within 6 days [47]. The report does not state the dose; the US label for oral risperidone recommends, in adult schizophrenia, starting at 2 mg/day, increases of 1 to 2 mg, a target dose of 4 to 8 mg/day and an effective range of 4 to 16 mg/day, and, in adolescents, starting at 0.5 mg with a target of 3 mg/day [62]. There are no specific data on the response to psychotropic drugs in HSS.

7.9 Drugs cited: doses and sources

7.10 Regulatory status

7.11 Evidence for interventions and trials

There are no clinical trials in HSS: a ClinicalTrials.gov search on 1 November 2026 returned no studies for "Hallermann", "Streiff" or "oculomandibulofacial" (the results for "Streiff" corresponded to a surname) [64]. The evidence on interventions comes from reports and series:

None of these studies has a comparison group, confidence intervals or standardised outcomes, and selective publication of cases with good results is likely; the results do not allow options to be compared with each other [40].

7.12 Gene therapy and investigational therapies

Without a causal gene, there is no target for gene therapy, gene editing or targeted molecular therapy, and there are no preclinical or clinical programmes directed at HSS. The CHD6 cellular model suggests autophagy and DNA damage response pathways, but has not given rise to therapeutic studies [7].

7.13 Developments in the last 12 months

Between November 2025 and November 2026 the review by Cavender and colleagues (February 2026), with proposed clinical criteria and an assessment framework, and the systematic review by Abbas and colleagues (June 2026), which emphasises NIV as first line for infant OSA and early assessment of the airway and eye, were published [4, 40]. A report of a periprosthetic femoral fracture and a correction to the article by Preudhomme and colleagues (September 2026) were also published [36, 65]. All are reviews and case reports; there were no trials, company announcements or regulatory decisions.

7.14 Agents and situations to avoid

There are no drugs specifically contraindicated by HSS. Anaesthesia without airway planning is the highest-risk situation, and the postoperative period requires prolonged saturation monitoring [14]. Somatropin should not be started without airway assessment, by analogy with Prader-Willi syndrome [60]. Pressure from spectacle frames on the atrophic nasal skin should be avoided [40].

7.15 Pregnancy, transition and adulthood

Spontaneous pregnancy in women with HSS has been described, and affected women have had healthy children [1, 3, 15]. Orphananesthesia has no data on obstetric anaesthesia, and the difficult airway, which worsens with age, should be assessed before delivery [14, 51]. In the transition to adulthood, surveillance of sleep (OSA may appear or worsen in adults), glaucoma and the cornea continues, and definitive maxillofacial and dental rehabilitation is concentrated after the end of growth [10, 15, 45, 59].

7.16 Recommendations and divergences

The sources agree on early assessment of the airway and eye and on early cataract surgery [4, 9, 15, 40]. They diverge on second-line management of infant OSA: tracheostomy was the most used option in published cases, whereas Guerin and colleagues and the review by Abbas propose NIV as the first option when ENT surgery is not sufficient [9, 15, 40]. On growth hormone, Cavender considers efficacy unknown, whereas Pivnick recommends endocrine assessment in the presence of signs of hypopituitarism, with no contradiction between the two [4, 19].

8. Reproductive Options and Family Counselling

8.1 Basis of counselling

Counselling starts from three facts: the cause is unknown, inheritance is not established and almost all cases are sporadic [1, 2, 4]. Risk figures therefore cannot be derived from a confirmed Mendelian model and are based on limited empirical observations, which should be presented as such.

8.2 Risk to siblings

For the healthy parents of a child with sporadic HSS, published experience shows rare recurrence: in the North American series of 15 patients none had affected siblings, and in the review of 24 patients published between 2003 and 2025 none had a family history [4, 15]. Sibling recurrence has, however, been described in consanguineous families (Bueno-Sanchez), in François' compilation (at least ten families with two or more cases, almost all in siblings) and in the lethal form of Dennis and colleagues, which leaves open autosomal recessive inheritance in some families or parental germline mosaicism [1, 6]. When the parents are consanguineous or recurrence has already occurred, the theoretical risk for each sibling is that of a recessive disorder (25%), assuming that model, and should be explained as a hypothesis [1, 4]. Monozygotic twins may be concordant or discordant, and one dizygotic pair was discordant [1, 27, 29].

8.3 Risk to the offspring of a patient

Women and men with HSS have had children: in the North American series, four of 15 patients had healthy children, and several women with HSS had offspring without transmission [4, 15]. Conversely, vertical transmissions have been described (Guyard's father and daughter; five cases in three generations with male-to-male transmission; father, daughter and granddaughter in Cameroon), compatible with autosomal dominant inheritance, which would imply a 50% risk for each child [1, 28]. In the family of Harrod and Friedman, the patient's mother, sister and son had only congenital cataract, of uncertain significance [26]. Information for the adult patient should include this range of possibilities and the recommendation of early ophthalmological assessment of any child [4, 26].

8.4 Cascade testing, carriers and prenatal diagnosis

Without an identified gene there is no cascade testing, carrier detection, molecular prenatal diagnosis or preimplantation genetic diagnosis. Exome or genome sequencing of the index case and parents is useful to exclude differential diagnoses of known gene, whose recurrence risk and reproductive options are defined (for example, autosomal dominant or recessive ODDD, autosomal recessive ZMPSTE24 deficiency) [4, 25, 33]. Fetal ultrasound may detect severe skeletal abnormalities such as those of the lethal form, without specificity [6].

8.5 Counselling of minors and of patients with visual impairment

Counselling of children and adolescents with HSS focuses on explaining the condition and surveillance, with reproductive information kept for the age at which it can be understood and decided upon by the individual. Severe visual impairment and, in a minority, intellectual disability require adapted materials [3, 4].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency

Orphanet classifies the prevalence as unknown [2]. About 200 patients have been published worldwide, a number that measures reports and not population frequency [4]. In 2018, Schmidt and Wollnik counted fewer than 200 individuals with a suggested diagnosis of HSS and considered that some of them correspond only to a spectrum of the syndrome or to another entity, an observation they also made in their own cohort [21]. The only population datum comes from a survey of 27 472 consecutive newborns in a large Tokyo maternity hospital, published in 1990, which recorded one case of HSS; Cavender and colleagues read it as an incidence of 1 in 27 472 births, but it is a single case in a hospital sample, without a useful confidence interval [4, 8]. A letter by Numabe and Kosaki (2021) on prevalence in the Japanese paediatric population is cited by Guerin and colleagues and by Ramírez and Davila as an estimate of 1 in 10 million; the two figures differ by more than two orders of magnitude and measure different things (one case in a hospital neonatal survey versus a national paediatric prevalence estimate) [4, 9, 36]. The sex ratio is close to 1 (42 males and 46 females in François' compilation; 10 and 14 in the 2026 review) [1, 4].

9.2 Geographical distribution and populations

HSS has been described on all continents. The 2026 systematic review included cases from Europe, Asia, Africa and the Americas [40]. In the USA, the Wake Forest series of 15 patients is the largest from a single centre, and reports include infants with fatal respiratory obstruction and twin girls of Filipino ancestry [15, 17, 18, 29]. In Europe there are reports and series from Belgium (six patients with corneal opacities), Germany (eight patients studied for laminopathies), Switzerland, France, the Netherlands and Spain [9, 24, 39, 41, 43, 45, 59]. In Japan, in addition to the neonatal survey, a patient diagnosed at 68 years and a study on reproductive success were published [8, 10, 66]. The familial cases with a dominant pattern include the family from Cameroon, and the cases with parental consanguinity include those from Pakistan (TRPM7 variant) and Brazil (patient excluded because of probable ODDD) [1, 4, 28, 32]. In Brazil, an adolescent with HSS and lower-limb lymphoedema was also published from São José do Rio Preto [46]. The sources consulted do not describe Portuguese patients or frequency data in Portugal or Brazil, and no founder population was identified.

9.3 Special populations

Severe visual impairment affects schooling and autonomy, and most patients have normal intelligence, which favours inclusive schooling with visual support [3, 4]. In settings with limited access to care, the diagnosis may be made only in adulthood, during a cataract screening campaign, as in the family from Cameroon [28]. Ethnic differences in facial morphology may modify the gestalt: Pivnick and colleagues attributed to ethnic background the less classic facial presentation of a Black boy [19].

9.4 Reference networks and patient organisations

Orphanet associates with HSS the ERN ITHACA (malformation syndromes, intellectual disability and other neurodevelopmental disorders), ERN-Skin (rare skin diseases), ERN BOND (rare bone diseases) and ERN-RND (rare neurological diseases), as well as national networks in France (AnDDI-Rares, DéfiScience, FIMARAD, OSCAR), Germany (DRN-HAUT, DRN-RND, NetsOs, dITHACA), Switzerland (SwissITHACA and Swiss networks for rare neurological and skin diseases) and the Netherlands (Radboudumc AGORA) [2]. Orphanet lists 477 expert centres, 107 diagnostic tests, 133 patient organisations (mostly generic or for rare diseases in general), 33 registries and one article for the public in Swedish (Socialstyrelsen, 2024) [2]. The Orphananesthesia anaesthetic recommendations are available in English and Czech [2, 14].

10. Illustrative Clinical Case

10.1 Infant with HSS and severe obstructive apnoea treated with non-invasive ventilation

Guerin and colleagues, from the Centre Hospitalier Universitaire Vaudois (Lausanne), published in 2022 the case of a girl born at 38 weeks after a normal pregnancy, with a weight of 3110 g (25th–50th centile), length of 47 cm (5th centile) and head circumference of 32.5 cm (5th centile) [9]. At birth she had a tiny nose with marked hypoplasia of the nasal cartilage and skin atrophy, micro-retrognathia, microcephaly, four neonatal teeth (upper and lower central incisors), bilateral congenital cataract, an atrial septal defect and two small apical ventricular septal defects; the diagnosis of HSS was clinical [9]. Exome sequencing, with analysis of 82 premature ageing genes and 1832 developmental disorder genes, identified no cause [9]. ENT endoscopy on the third day showed narrow but patent choanae, without laryngotracheomalacia or adenotonsillar hypertrophy, and overnight oximetries on the fourth day and at 5 months were normal [9].

In the following months, neurodevelopmental delay and failure to thrive appeared because of multifactorial feeding difficulties, daily aspiration and severe gastro-oesophageal reflux [9]. At 8 months, admitted for investigation, she had axial hypotonia (poor head control, unable to sit), good grasp and good interaction despite the visual impairment; apnoeas were observed, and polygraphy showed severe OSA, with an obstructive AHI of 25 per hour and 0.4% of the night with oxygen saturation below 90%, without hypercapnia [9]. Repeat endoscopy revealed still narrow choanae and adenoid hypertrophy; adenoidectomy and surgical gastrostomy (without antireflux surgery) were performed, with a weight of 3870 g, below the 3rd centile [9].

Six weeks later, snoring and fragmented sleep persisted and polygraphy showed worsening, with an obstructive AHI of 140 per hour and 41% of the night with saturation below 90% [9]. Tracheostomy was proposed, but after discussion between the parents, ENT, maxillofacial surgery, intensive care, respiratory medicine and physiotherapy, it was decided to try nocturnal NIV at 10 months (4450 g and 59.5 cm), in an intermediate care unit [9]. Nasal CPAP was well tolerated but did not improve the obstruction, and increasing the expiratory pressure was poorly tolerated; she was switched to BPAP in spontaneous mode, with a single circuit and a paediatric nasal mask, titrated to an expiratory pressure of 5 and an inspiratory pressure of 9 cmH2O, and enteral feeding was restricted to daytime to reduce the risk of aspiration [9]. After 5 days, the obstructive AHI was 7.6 per hour, with 1% of the time below 90% saturation [9]. The polygraphic tracing before and on NIV is shown in figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC9669373/figure/F1/), which shows frequent hypopnoeas with desaturations without ventilation and regular breathing without obstructive events on BPAP [9].

The child was discharged with the parents trained in NIV and gastrostomy care; over the following year there were no adverse events, median use was 8 hours per night and no adjustments were needed [9]. One year later, polygraphy on NIV showed an AHI of 1.4 per hour and less than 1% of the time with saturation below 90%; maxillofacial assessments showed no facial deformation attributable to the mask, and the parents reported rapid improvement in psychomotor milestones, interaction and behaviour [9]. At 2 years, neurodevelopment corresponded to that of a 12-month-old child [9].

10.2 Clinical reading of the case

The case illustrates three aspects of HSS: OSA may appear or worsen rapidly in the first months, normal overnight oximetry does not exclude it and adenoidectomy may not be sufficient [9]. The choice of NIV instead of tracheostomy resulted from a multidisciplinary decision in a centre experienced in paediatric ventilation and with motivated parents, and the authors present it as a bridge to future maxillofacial surgery; tracheostomy remains the most used option in published cases, and the success of an isolated case does not establish NIV as routine management [9, 15]. The facial image of a child with HSS (blue sclerae, strabismus, thin nose with small alae, small receding mandible, sparse hair, eyebrows and eyelashes) is reproduced in the 2026 review (https://pmc.ncbi.nlm.nih.gov/articles/PMC13628979/figure/Fig2/) [4].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

Vital prognosis depends mainly on the airway in the first year: deaths at 6 and 11 months from respiratory failure, cor pulmonale and aspiration have been published, as well as one postoperative death from respiratory compromise in the series of 15 patients, three of whom required tracheostomy [15, 17, 18]. The 2026 systematic review reports partial improvement with multidisciplinary treatment in most cases and mortality in severe neonatal respiratory failure [40]. Beyond childhood, survival may extend into the seventh and eighth decades (patients aged 68 and 77 years) [10, 28]. There are no formal studies of life expectancy after childhood; Schmidt and Wollnik accept that airway complications and the early onset of age-related diseases may shorten it, without data to quantify this [21]. Functional prognosis depends on vision: the ocular defect often culminates in blindness despite surgery, and surgical series describe moderate improvement (median 20/380 in a series of four children; 20/130 to 20/260 in the twins at 4–5 years) with frequent complications (glaucoma in three of six Belgian patients, retinal detachments, corneal perforation) [3, 29, 37, 39]. Most have normal intelligence, with intellectual disability in about 15% [1, 3]. Mean final height is 152 cm in women and 155 to 157 cm in men [3]. The severe form described by Dennis and colleagues is lethal [6].

11.2 Surveillance table

There are no validated surveillance intervals for HSS; the table brings together the recommendations of the sources and indicates when the interval has not been published.

12. Summary and Final Considerations

Hallermann-Streiff syndrome is a malformation syndrome of clinical diagnosis, defined by the association of congenital cataract and/or microphthalmia with a characteristic face (thin pointed nose, micrognathia or retrognathia, brachycephalic skull with bossing) and by at least two of four additional features: proportionate short stature, hypotrichosis, skin atrophy and dental anomalies. About 200 patients have been published, almost all sporadic, and prevalence is unknown. Almost eight decades after the descriptions by Hallermann and Streiff there is no established gene: the variants described in GJA1, ZMPSTE24, LMNA and TRPM7 correspond to alternative diagnoses or have not been replicated, and the de novo CHD6 variant, studied in a cellular model that points to changes in autophagy and the DNA damage response, remains confined to a single patient. Inheritance remains undetermined, with families showing a dominant pattern, sibships with consanguinity and numerous isolated cases.

Management is symptomatic and multidisciplinary. The narrow upper airway is the main cause of death in childhood and requires ENT assessment and a sleep study from the first months, planning of any anaesthesia and individual choice between ENT surgery, non-invasive ventilation, tracheostomy and maxillofacial surgery. The ocular defect is the main cause of disability and calls for early cataract surgery, surveillance for glaucoma, uveitis, corneal and retinal complications, and visual rehabilitation. Preventive dental care, growth monitoring with endocrine assessment when indicated and maxillofacial reconstruction after growth complete the plan. The differential diagnosis with oculodentodigital dysplasia, the progeroid syndromes and gracile bone dysplasia, supported by exome or genome sequencing, avoids labelling disorders of known gene as HSS and is also the path towards identifying the cause.

13. References

1. Online Mendelian Inheritance in Man (OMIM). %234100 Hallermann-Streiff syndrome; HSS. Baltimore: Johns Hopkins University; last edited 16/09/2025. Available from: https://www.omim.org/entry/234100
2. Orphanet. Hallermann-Streiff syndrome (ORPHA:2108). Version 1.6.11, updated 2026-10-21. Available from: https://www.orpha.net/en/disease/detail/2108
3. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 132–133.
4. Cavender C, Atzinger C, Slavotinek A. A review of Hallermann-Streiff syndrome demonstrates clinical overlap with other conditions. Orphanet J Rare Dis. 2026;21(1):333. doi:10.1186/s13023-026-04277-7
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