GUBS and Other PPP1R12A-Related Disorders

Congenital malformation syndrome caused by heterozygous, almost always de novo, loss of function of the PPP1R12A gene, which encodes the regulatory subunit of myosin phosphatase; the spectrum ranges from isolated 46,XY difference of sex development or persistence of Müllerian derivatives to holoprosencephaly and anencephaly, with intestinal atresias and ocular, skeletal and auditory anomalies.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition

Genitourinary and/or brain malformation syndrome (GUBS) is an autosomal dominant disease caused by heterozygous loss-of-function variants in the PPP1R12A gene, which encodes MYPT1 (myosin phosphatase target subunit 1), the regulatory subunit of myosin phosphatase [1, 2]. The most frequent manifestations lie in two embryonic territories: the urogenital tract, with differences of sex development (DSD) in 46,XY individuals ranging from hypospadias to complete gonadal dysgenesis with female external genitalia, and the forebrain, with midline malformations that include holoprosencephaly (HPE) [12]. Some patients have only one of the two components, and reports after 2020 added gastrointestinal tract atresias, persistence of Müllerian derivatives with complete external virilisation, growth hormone deficiency, sensorineural deafness with inner ear malformation and a fetal perineal mass [3, 13–15, 21].

GeneReviews uses the designation PPP1R12A-related urogenital and/or brain malformation syndrome (UBMS) and defines the diagnosis by the combination of suggestive findings with a heterozygous pathogenic or likely pathogenic PPP1R12A variant; there are no consensus clinical criteria [2]. The terms GUBS and UBMS designate the same entity, and the literature uses both.

1.2. Founding article and milestones

In December 2019 (January 2020 issue), Hughes, Alkhunaizi, Kruszka and colleagues, drawing on two independent next-generation sequencing projects, one in HPE and the other in DSD, and on international collaboration through GeneMatcher, described 12 individuals with loss-of-function variants in PPP1R12A, a gene with no previous association with human disease [12]. Two came from a cohort of 277 patients with HPE (135 trios and 142 singletons) without variants in SHH, ZIC2, SIX3 or TGIF1; eight came through GeneMatcher; and two were found by targeted search in a DSD cohort of 94 families (300 individuals) [12]. The participating centres were in the United States, Canada and Germany [12]. The title of the article, «from isolated sex reversal to holoprosencephaly spectrum and urogenital malformations», summarises the phenotypic breadth that remains the defining feature of the syndrome.

OMIM created the phenotype entry 618820 with the designation GUBS, and GeneReviews published the dedicated text on 9 September 2021, revised on 7 March 2024; the 2024 revision removed the information on 46,XX individuals that appeared in the initial version [1, 2]. In 2022, Picard, Josso and colleagues, on exome reanalysis of 24 patients with persistent Müllerian duct syndrome (PMDS) without biallelic AMH or AMHR2 variants, found truncating PPP1R12A variants in five (21%), the first gene outside the anti-Müllerian hormone (AMH) pathway associated with this syndrome [3]. Between 2023 and 2026 a succession of reports broadened the spectrum: intronic variants with a splicing effect demonstrated by minigene or by patient RNA, neonatal epilepsy, monozygotic twins with discordant genital phenotypes, jejunal atresia with growth hormone deficiency, deafness with cochlear malformation and a stop-loss variant in two patients with jejunal atresia [8, 9, 14, 15, 21–23].

1.3. Nomenclature and classification

GUBS has no formal subtypes. By type of DSD, 46,XY patients with undervirilisation and dysgenetic gonads resemble partial or complete gonadal dysgenesis, whereas those with complete external virilisation, normal AMH and Müllerian derivatives meet the clinical criteria for PMDS [3, 23]. In the GeneReviews HPE overview, PPP1R12A appears among the rare genes, with «broad spectrum of craniofacial features» and «HPE, urogenital malformations and developmental delay» as the phenotype [11]. In this article, for clinical convenience and without formal nosological value, three predominant presentations are distinguished: urogenital (46,XY DSD with or without gonadal dysgenesis), neurological (midline brain malformation, delay, epilepsy) and mixed; the form with PMDS and intestinal atresia is treated as part of the urogenital spectrum.

1.4. Scope of the article

The article covers GUBS due to point and intragenic variants, 12q21 deletion as a related genetic disease and somatic PPP1R12A alterations in tumours. HPE in general, with the genes SHH, ZIC2, SIX3, TGIF1 and the others, the general approach to DSD, 46,XY gonadal dysgenesis, including the risk of germ cell tumour and puberty induction, PMDS due to AMH and AMHR2, which includes PPP1R12A-associated PMDS, and androgen insensitivity enter the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The PPP1R12A gene and the MYPT1 protein

PPP1R12A lies at 12q21.2–q21.31, spans about 162 kb and has 25 exons, with several isoforms produced by alternative splicing; the MANE Select transcript is NM_002480.3, which encodes a protein of 1030 amino acids (NP_002471.1; UniProt O14974) [3, 6, 7, 22]. The protein, MYPT1, is the regulatory and targeting subunit of myosin phosphatase, a trimeric holoenzyme combining MYPT1, the catalytic subunit of protein phosphatase 1 (PP1c, in the PP1cβ isoform, encoded by PPP1CB) and a small subunit of poorly understood function, M20/21 [3, 8, 12]. Myosin phosphatase removes the phosphate from the regulatory light chain of smooth muscle and non-muscle myosin II, thereby opposing the myosin kinases; the balance between the two activities controls actomyosin contractility, cell shape, migration and adhesion [3, 6, 12].

The structure of MYPT1 explains the effects of truncating variants. The N-terminal region contains the PP1c-binding motif (KVKF, of the RVxF type) and eight ankyrin repeats; the central region contains the interaction domain for the Rho-associated kinases (ROCK1 and ROCK2), which phosphorylate MYPT1 at threonines 696 and 853 and inhibit the phosphatase; the C-terminal region contains a leucine zipper that binds cyclic GMP-dependent protein kinase [3, 8, 12]. MYPT1 acts as a platform that brings the catalytic subunit to substrates not limited to the myosin light chains and directs it to specific cellular compartments, which gives it roles in the cell cycle, neurotransmitter release and the regulation of gene expression [3, 15]. MYPT1 is widely expressed, including in the brain, thyroid, kidney, urinary tract, small intestine, endometrium and fallopian tubes, whereas the paralogues MYPT2 and MYPT3 predominate in the heart and skeletal muscle [3, 22].

2.2. Disease mechanism

The established mechanism is loss of function through haploinsufficiency [2]. The gene is intolerant of loss of function: in gnomAD, at the time of the founding article, 3 loss-of-function variants were observed against 59.8 expected (observed/expected ratio 0.05), and the current indices cited in 2026 are pLI 1 and LOEUF 0.2 [12, 24]. Nonsense and frameshift variants generate premature termination codons subject to nonsense-mediated mRNA decay (NMD), predicted but rarely demonstrated; elimination of one of the myosin phosphatase subunits reduces expression of the other, which decreases holoenzyme activity [12]. In an overexpression system in HEK293T cells, the p.(Arg845Ter) variant produced a truncated protein of about 96 kDa that no longer co-immunoprecipitated with PPP1CB, and the molecular dynamics model predicted an increase of about 50% in the binding free energy of the complex [8]. In mice with conditional inactivation of Mypt1 in smooth muscle, phosphorylation of the myosin regulatory light chain and vascular contractility increased and the animals developed permanent hypertension without structural vascular changes, which documents the role of MYPT1 in vascular tone [5]. Mice heterozygous for constitutional inactivation of Ppp1r12a have no relevant phenotype and homozygotes die before the seventh day post-conception, an observation cited to allow for mechanisms beyond haploinsufficiency [8, 12].

2.3. Pathophysiology by territory

Forebrain. In the mouse, Ppp1r12a is expressed in the prosencephalic neural folds at gestational day 8.25, in the cephalic mesenchyme, with a pattern similar to that of Gli2, during the critical period of forebrain division [12]. In zebrafish, morpholino knockdown of ppp1r12a causes gastrulation defects, deficient anterior migration of the prechordal plate, complete or partial cyclopia and microphthalmia; removal of the prechordal plate produces cyclopia, which links the failure of cell migration to HPE [12]. The available evidence does not place PPP1R12A in the canonical HPE pathways, such as the sonic hedgehog pathway, but in a mechanism of migration and cytoskeletal organisation [12].

Urogenital tract. In the mouse, the protein is located in the epithelium of the bladder, urethra and genital tubercle at days 13–13.75; in 10-week human embryos, in the epithelium of the genital tubercle, bladder and urethra, in the mesenchymal cells of the urogenital sinus and in the detrusor, whereas the paralogue PPP1R12B is confined to detrusor smooth muscle [12]. Three mechanisms explain the genital spectrum. The first is gonadal dysgenesis, with early loss of Sertoli and Leydig cells, which explains the streak gonads, low AMH and undervirilisation in some 46,XY patients [12, 23]. The second is failure of Müllerian regression with preserved testicular function: regression requires coelomic epithelial cells bearing the AMHR2 receptor to undergo epithelial-mesenchymal transition and migrate into the peri-Müllerian mesenchyme, a process dependent on cell motility and, hypothetically, on intact myosin phosphatase; this hypothesis has not been tested experimentally, and an alternative is an effect on AMH signal transduction [3, 23]. The third is an alteration in the formation of the Müllerian ducts, which depend on RhoA GTPases for invagination and apical constriction [12, 14]. Expression of Ppp1r12a in mouse smooth and striated muscle is higher in males during sexual differentiation, and the predominance of 46,XY patients in the series may reflect ascertainment bias or a sex-influenced mechanism [12].

Gastrointestinal tract. Small intestinal atresias have been attributed to an intrauterine mesenteric vascular accident; since MYPT1 controls vascular smooth muscle relaxation, loss of function would increase vasoconstriction, a hypothesis that Picard and colleagues put forward for the jejunal and oesophageal atresias of their patients [3]. A medaka model obtained by chemical mutagenesis, with a nonsense variant in mypt1, develops embryonic intestinal atresia with ectopic accumulation of F-actin and phosphorylated myosin light chain in the intestinal epithelium and epithelial disorganisation, without changes in proliferation, motility or apoptosis; inhibition of myh11a (smooth muscle myosin) attenuates the phenotype and blebbistatin, a myosin II inhibitor, rescues it completely, which suggests a non-contractile role preceding smooth muscle maturation [25]. These data are preclinical.

Inner ear. The RhoA/ROCK pathway participates in the morphogenesis of cochlear hair cells, and Ppp1r12a is expressed in the cochlear and vestibular sensory epithelium of the mouse and in the human fetal inner ear at 7.5 and 9.2 weeks, which makes the cochleovestibular malformation described in 2026 biologically plausible [15].

2.4. Variant spectrum

In 2026, Pianigiani and colleagues compiled 24 pathogenic or likely pathogenic variants: 11 nonsense (45.8%), 7 frameshift (29.2%), 4 splicing (16.7%), one stop-loss (4.2%) and one complex rearrangement (4.2%), distributed throughout the gene without clustering in exons or domains [15]. The following table brings together variants of particular clinical or mechanistic significance, normalised in VariantValidator on the MANE transcript [7].

Two variants require cautious interpretation. The stop-loss variant c.3092A>T was classified as a VUS by the laboratory of the second patient, although recurrence in two patients with jejunal atresia strengthens the association [14]. The missense variant c.38A>G was excluded from the 2026 compilation for lack of functional evidence and of a proposed mechanism, because the disease is caused by loss of function [15, 21]. Reports with non-canonical intronic variants (c.792+3A>C, c.2666+3A>G, c.2462-11A>G) show that RNA analysis, by minigene or in blood, allowed variants of uncertain significance to be reclassified [9, 15, 22]. In October 2026, ClinVar had 365 records for the gene, of which 57 were pathogenic or likely pathogenic and 174 of uncertain significance [29].

2.5. Inheritance, penetrance and expressivity

All variants studied in the parents were de novo; in a review of 23 cases, 15 of 15 tested [2, 9]. No vertical transmission has been published, nor has parental mosaicism been documented [2]. Expressivity is highly variable: the monozygotic twins with the same c.1551-2A>G variant were discordant: one had gonadal dysgenesis with AMH of 0.02 ng/mL and the other functioning testes with AMH above 23 ng/mL [23]. No genotype-phenotype correlations have been identified, either by position or by type of variant [2, 9, 12, 15]. As heterozygous mice have no phenotype and there are adults with complete virilisation and normal intelligence, penetrance of the severe manifestations is incomplete, and the absence of obvious anomalies in 46,XX individuals may lead to underdiagnosis [3, 8, 9].

2.6. Related genetic diseases

12q21 deletion. Deletions of the 12q21 region are rare and non-recurrent [4]. Niclass and colleagues described three patients, including the first diagnosis by array comparative genomic hybridisation (array-CGH) during pregnancy, and defined a minimal critical region of 1.6 Mb with the candidate genes SYT1 and PPP1R12A [4]. Recalcati and colleagues, with seven Italian cases, placed SYT1, PAWR, PPP1R12A and OTOGL in that region; the smallest deletion recorded in DECIPHER, of 257 kb, covers only exons 2–25 of PPP1R12A [30]. The phenotype includes developmental delay, ectodermal anomalies, ventriculomegaly or hydrocephalus, axial hypotonia or spastic diplegia, growth retardation, heart disease, hydronephrosis, vesicoureteric reflux or horseshoe kidney, broad chest or pectus excavatum, 2–3 toe syndactyly, pterygium colli, large anterior fontanelle and facial dysmorphism with hypertelorism, a short upturned nose and micro-retrognathia [4]. GeneReviews counts 14 individuals with deletions including PPP1R12A, none with 46,XY DSD [2]. Recalcati and colleagues attribute the neurodevelopmental component mainly to SYT1 and the malformations and dysmorphism mainly to PPP1R12A; the ectodermal anomalies are not explained by either gene [30]. Di Nora and colleagues added CEP290 to the genes involved in most published deletions [31].

Somatic alterations. PPP1R12A copy number has been associated with recurrence and survival in stage III colorectal cancer treated with oxaliplatin, and fusions involving PPP1R12A at 12q21.1–q21.31 have been described in alveolar and sarcomatoid rhabdomyosarcomas of the bladder; these alterations are not in the germline and do not confer hereditary predisposition [2].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and limitations

All clinical information comes from case reports and small series, with no prospective cohorts or natural history studies. The founding series has 12 individuals (United States, Canada, Germany), ranging in age from a 12-week fetus to a 45-year-old adult [12]; Picard's series has five patients with PMDS (France, the Netherlands), born between 1989 and 2005 [3]; and later reports come mainly from China, the United States, Italy, Switzerland and Mexico [8, 9, 13–15, 21–24, 26, 27]. Many assessments are incomplete (karyotype, pelvic imaging, nature of the gonads, brain magnetic resonance imaging (MRI)), so the frequencies are minimum figures and depend on the mode of ascertainment: HPE series collect patients with brain malformation, and DSD series collect patients with genital anomalies [12, 23].

The difference between the two reviews in gastrointestinal anomalies results from the criteria: the review of 22 cases by Gomes and colleagues counted jejunal and ileal atresias, oesophageal atresia and rectoperineal fistula, including Picard's patients [9, 14].

3.2. Urogenital system and sex development

46,XY DSD and genitourinary anomalies are the main manifestations [2]. The external genitalia of 46,XY individuals range from mild to severe undervirilisation, with micropenis, chordee, hypospadias of variable degree (glandular, penile or scrotal), bifid and high-inserted scrotum, urogenital sinus anomalies, anteriorly placed anus and, at the extreme, normal-appearing female external genitalia [2]. In the founding series, three 46,XY individuals had female external genitalia [12]. The gonads range from cryptorchidism to complete gonadal dysgenesis, with streak gonads in severe cases; Müllerian structures (fallopian tubes, uterus, upper vagina) may be present [2]. In 9 of 14 46,XY individuals assessed by Tian and colleagues, the Müllerian derivatives had not fully regressed, and 6 of 11 with undervirilisation had testicular dysgenesis [23].

The 46,XY patients of the founding series illustrate the spectrum: micropenis, chordee, scrotal hypospadias, bilateral cryptorchidism and uterus at 3 years; glandular hypospadias and chordee at 6 years; hypospadias, cryptorchidism, uterus and ovaries (gonads described as ovaries) at 7 years; uterus didelphys and streak gonads in a 45-year-old woman; clitoral hypertrophy, urogenital sinus and posterior fusion of the labia majora at 2 years; grade 2 hypospadias, cryptorchidism, uterus and an inguinal hernia containing a fallopian tube at 2 years; streak gonads with rudimentary fallopian tubes and urogenital sinus at 12 years; and clitoris, posterior labial fusion, labial rugosity and pigmentation, uterus, fallopian tubes and ovaries at 3 years [12]. Seven of the 12 individuals had a female phenotypic sex, four of whom had a 46,XY karyotype, the number OMIM adopts for 46,XY individuals with female external genitalia, whereas the text of the article mentions three [1, 12]. OMIM stresses the limits of ascertainment in the founding series: two of the three 46,XX individuals were not assessed from a genitourinary point of view, in the third the autopsy did not describe those structures, and three 46,XY individuals had no brain assessment, so the hypothesis of a sex-influenced mechanism remains unproven [1]. OMIM describes patient 11 as 30 years old, with streak gonads, rudimentary fallopian tubes, urogenital sinus without uterus, alopecia totalis, obesity, acanthosis nigricans and developmental delay, whereas the table in the article gives her age as 12 years [5, 12].

Picard and colleagues described a different genital phenotype: five 46,XY patients with fully virilised external genitalia, no signs of Leydig cell deficiency, cryptorchidism, uterus and fallopian tubes, and AMH normal for age in the three in whom it was measured (122.80 pmol/L; 201 pmol/L at 3 days; 171.36 pmol/L at 7 years) [3]. One of these patients had transverse testicular ectopia with a uterus in an inguinal hernia, a typical presentation of PMDS [3]. Voide and colleagues documented, in a 46,XY newborn with PMDS, a genital tubercle of 2.5 × 0.9 cm, an apical meatus, impalpable gonads and a Müllerian duct of 2.5 × 1 cm, with normal minipuberty and a fall in AMH and inhibin B below the reference values at 10 months, consistent with emerging Sertoli cell dysfunction [24]. In the monozygotic twins of Tian and colleagues, the same variant was associated with gonadal dysgenesis with Prader stage III in one and with functioning testes with severe hypospadias (Prader IV) in the other, both with a uterus [23]. The 46,XY patient of Contreras-Capetillo and colleagues had a female phenotype, ovotestis, absence of Müllerian derivatives and testicular atrophy [24, 27].

Gonadal function may deteriorate after birth. One of Picard's patients with normal testosterone (21.8 nmol/L) at 22 years developed hypergonadotrophic testicular failure with azoospermia six months after an orchidopexy, with loss of both testes; another, with spontaneous puberty, retained at 18 years a 20 mL testis and testosterone of 22.88 nmol/L after removal of the involuting right testis [3].

In 46,XX individuals, information is scarce. The three 46,XX individuals in the founding series had severe brain malformation (HPE or anencephaly) and were not assessed genitally [12]. Subsequently described were a 46,XX newborn girl with vaginal atresia and normal-appearing uterus, fallopian tubes and ovaries [14], a newborn girl with normal female genitalia and epilepsy [8, 14] and a 46,XX fetus with a 20 × 15 mm perineal hamartoma under the left labium majus, with normal external genitalia [13]. Bland and colleagues allow that 46,XX women without other anomalies may be asymptomatic and under-reported [9].

Kidney and urinary tract. Duplex collecting system, renal asymmetry, pyelectasis, megaureter with ureterocele and solitary kidney have been described [2, 12, 14, 15].

3.3. Central nervous system and neurodevelopment

Brain malformations are variable, and the most severe belong to the HPE spectrum and are associated with moderate to profound intellectual disability, epilepsy and feeding difficulties [2]. In the founding series, there was HPE of the middle interhemispheric variant (syntelencephaly), with polymicrogyria and Chiari I malformation, in a 15-year-old girl with intellectual disability, attention deficit hyperactivity disorder (ADHD) and seizures; semilobar HPE with agenesis of the corpus callosum in another 15-year-old, with myoclonus, intellectual disability and toe syndactyly; agenesis of the corpus callosum with colpocephaly; acrania with exencephaly in a 12-week fetus; dysgenesis of the corpus callosum, absent septum pellucidum, Chiari malformation, cortical dysplasia and grey matter heterotopia; and leukomalacia [12]. Other reports add semilobar HPE with fusion of the frontal lobes and acquired microcephaly [9], middle interhemispheric HPE with hypersynchronous electroencephalographic patterns [32], cerebellar heterotopias in a stillborn infant [3], a thin corpus callosum with white matter and cerebellar lesions [8] and a hypoplastic corpus callosum with delayed myelination [15].

Development ranges from normal intelligence to severe impairment [2]. ADHD, autistic traits and autism spectrum disorder, dystonia, appendicular hypotonia with foot pronation, unsteady gait, spastic tetraparesis and epilepsy have been described [2, 9, 14]. Several patients with the urogenital form or with PMDS have normal development: one of Picard's patients was undertaking postgraduate studies, and another, at 29 years, reported normal physical and mental health [3]; the 11-year-old boy of Saul and colleagues had above-average school performance [21].

Epilepsy. Epilepsy has been described in patients with brain malformation [2, 9, 12]. A newborn girl with the p.(Arg845Ter) variant had tonic-clonic seizures on the second day and myoclonus on the seventh, with an electroencephalogram (EEG) showing bilateral asynchronous activity and generalised sharp waves, in a context of perinatal distress and possible cerebellar haemorrhages, which limits the attribution of the epilepsy to the gene [8]. In the patient with middle interhemispheric HPE, the EEG showed abundant hypersynchronous rhythmic theta activity in the centroparietal regions, hypersynchronous rhythmic beta and alpha activity and periods of voltage attenuation [32].

3.4. Gastrointestinal tract and feeding

Small intestinal atresias are the most frequent digestive anomaly: jejunal and ileal atresia with aberrant mesenteric blood supply in the founding series; type III or IIIb jejunal atresia, with malrotation or multiple stenoses, in three of Picard's five patients; partial oesophageal atresia in the fourth; type IIIb jejunal atresia with incomplete rotation, imperforate anus without fistula and vaginal atresia in a newborn girl with the c.3092A>T variant; proximal jejunal atresia with rectoperineal fistula in a 46,XY patient with the same variant; and jejunal atresia with resection on the second day in a boy with growth hormone deficiency [3, 12, 14, 21]. Other findings include omphalocele and gastrointestinal dysmotility [9, 12]. In the general population, small intestinal atresia has a birth prevalence of about 1.6–2.9 per 10,000 births and is associated with trisomy 21 in 15.2% of cases and with chromosomal anomalies in about 20%, according to the studies cited by Gomes and colleagues [14].

In severe brain malformation, feeding is difficult; newborns with feeding difficulties may develop hyperbilirubinaemia; feeding often improves in the first months and typically worsens if seizures develop, with intercurrent illness and with growth [2]. Central hypotonia is associated with constipation [2]. A girl with semilobar HPE required a gastrostomy for dysphagia and faltering growth and was admitted at 11 years with chronic vomiting and severe malnutrition [9].

3.5. Growth, endocrine system and prematurity

Intrauterine growth restriction, microcephaly, macrocephaly, faltering growth and reduced subcutaneous tissue have been described [2]. Prematurity was recorded in all five of Picard's patients (34–37 weeks) and in eight of the 22 cases reviewed by Gomes and colleagues, including one born at 27 weeks [3, 14]. An 11-year-old boy with jejunal atresia had short stature (0.37th centile), delayed bone age, insulin-like growth factor 1 (IGF-1) of 88 ng/mL and growth hormone peaks of 6.9 ng/mL (clonidine) and 1.7 ng/mL (glucagon), with a small anterior pituitary, interrupted stalk and ectopic posterior pituitary on MRI [21]. In a series of 16 patients with pituitary stalk interruption syndrome studied by exome sequencing, none had a PPP1R12A variant, according to Saul and colleagues [21].

3.6. Eyes, hearing, face, limbs and other systems

Eyes. Strabismus, astigmatism, hypermetropia, unilateral or alternating esotropia, cone-rod dysfunction, low vision, latent nystagmus, microphthalmia or anophthalmia, optic nerve hypoplasia and severe unilateral myopia [2, 9, 12, 15].

Hearing. A 12.5-year-old Italian boy had profound bilateral sensorineural deafness detected on newborn screening, with a bilateral common cochleovestibular cavity, aplasia of the lateral and posterior semicircular canals and an enlarged vestibular aqueduct; he received bilateral cochlear implants at 18 months, with a good outcome [15]. A patient with HPE and a nonsense variant had a history of bilateral sensorineural deafness, without inner ear malformation, according to the description cited by Pianigiani and colleagues [15]. GeneReviews, which predates these reports, considers deafness a non-primary feature [2].

Face. The features described are non-specific and include a long face, facial asymmetry, arched or thick eyebrows, hypertelorism or hypotelorism, ptosis, long or short palpebral fissures, epicanthus or epicanthus inversus, a short upturned nose, micrognathia, large, low-set and prominent ears, preauricular pit, ear lobe creases and a long philtrum [2, 9, 12, 21]. Hypotelorism accompanies HPE, whereas other patients have hypertelorism [9].

Limbs and skeleton. Fifth-finger clinodactyly, toe syndactyly, bilateral postaxial polydactyly of the hands, ulnar deviation of the hand, kyphoscoliosis, joint contractures and stiffness, possible cervical fusion anomalies and absence of a hand [2, 9, 12, 14].

Heart and skin. Patent ductus arteriosus, muscular ventricular septal defect, patent foramen ovale and mild peripheral pulmonary artery branch stenosis [2, 14, 21]. The newborn girl of Gomes and colleagues also had arterial hypertension [14]. Multiple superficial infantile haemangiomas and a lumbar haemangioma, alopecia totalis and acanthosis nigricans [14, 27].

3.7. 12q21 deletion

Patients with a 12q21 deletion including PPP1R12A share dysmorphism and brain and urogenital defects, but, unlike GUBS due to point variants, have no recorded 46,XY DSD and frequently have ectodermal anomalies, hydrocephalus or ventriculomegaly and heart disease [2, 4, 30]. The picture depends on the size of the deletion and on the other genes lost, especially SYT1 [30].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Prenatal period. Suspicion arises in the presence of HPE or acrania/exencephaly, dilated bowel loops suggestive of atresia, with or without polyhydramnios, or discordance between the chromosomal sex obtained on screening or prenatal karyotype and the fetal genitalia [3, 12, 21]. An isolated solid perineal mass in a 46,XX fetus led to diagnosis by exome sequencing on amniotic fluid [13].

Newborn. The most suggestive picture is the combination of atypical genitalia in a 46,XY newborn (micropenis, hypospadias, bifid scrotum, urogenital sinus, impalpable gonads) with another malformation: midline brain malformation, intestinal or oesophageal atresia, omphalocele, renal or ocular anomaly [2, 3, 12]. In a newborn with intestinal or oesophageal atresia, the presence of Müllerian derivatives or 46,XY DSD points to PPP1R12A, because these digestive anomalies are not described in PMDS due to AMH or AMHR2 [3]. Prematurity and growth restriction accompany many of these newborns [3, 14].

Childhood and adolescence. Grounds for suspicion are cryptorchidism or inguinal hernia with a uterus or fallopian tube in the hernial sac, 46,XY DSD with normal AMH without AMH or AMHR2 variants, absence of puberty in a 46,XY girl with streak gonads, and developmental delay with brain malformation and genital anomaly [3, 12]. Short stature with growth hormone deficiency and a history of jejunal atresia, even without genital anomalies, prompted the diagnosis in an 11-year-old boy [21].

Adult. The form with complete virilisation may remain undiagnosed until surgery for an inguinal hernia or cryptorchidism, or until investigation of infertility or primary amenorrhoea [3, 12].

4.2. Warning signs and urgent situations

Intestinal and oesophageal atresias, imperforate anus and respiratory failure in preterm infants are neonatal emergencies, and led to surgery or ventilation in the first days in several reports [3, 8, 9, 14]. In 46,XY DSD with atypical genitalia, the full diagnostic assessment (physical examination, biochemistry, genetics and imaging) is discussed by the multidisciplinary team [33]; in the twins of Tian and colleagues, 17-hydroxyprogesterone, adrenocorticotrophic hormone and cortisol were measured and were normal [23]. Neonatal seizures, feeding difficulties with aspiration and hyperbilirubinaemia require immediate assessment [2, 8]. Loss of testicular function after orchidopexy, documented in an adult, justifies endocrine surveillance of retained gonads [3].

4.3. Newborn screening

There is no newborn screening for GUBS. Universal newborn hearing screening detected the profound deafness of the patient with inner ear malformation [15].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no consensus clinical criteria. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic PPP1R12A variant; a VUS neither establishes nor excludes the diagnosis [2]. The suggestive findings listed by GeneReviews are atypical external genitalia in 46,XY individuals, microcephaly or macrocephaly with developmental delay, intellectual disability or autistic traits, brain malformations, ocular and skeletal anomalies and, on imaging, alobar, semilobar or middle interhemispheric HPE, corpus callosum anomalies, anencephaly, cortical dysplasia, Müllerian remnants in 46,XY individuals and structural renal anomalies [2].

5.2. Clinical, imaging and biochemical assessment

The genital examination records palpation of the gonads in the labioscrotal folds, the length and width of the phallus, chordee, the foreskin, the location of the urethral meatus, the anogenital distance, the presence of a vaginal dimple or introitus, and the fusion, rugosity and pigmentation of the labioscrotal folds [2]. The Prader and external masculinisation score (EMS) scales quantify virilisation; in the twins of Tian and colleagues, the EMS was 0 in one and 5.5 in the other [23]. Renal, abdominal and pelvic ultrasound looks for renal anomalies and Müllerian structures; MRI or laparoscopy clarifies the internal anatomy, and urethrocystoscopy assesses the urogenital sinus [2, 23, 24]. Brain MRI and, if there are seizures, EEG are part of the neurological assessment [2].

GeneReviews proposes hormonal studies between 2 weeks and 3 months of life, during minipuberty, and at pubertal age, with total testosterone, dihydrotestosterone, inhibin B, AMH, follicle-stimulating hormone (FSH) and luteinising hormone (LH) [2]. The profile distinguishes two patterns. In gonadal dysgenesis, gonadotrophins are raised and AMH, inhibin B and testosterone are low, with no response to human chorionic gonadotrophin (hCG): in one of the twins, FSH was 140.22 IU/L, LH 26.23 IU/L, AMH 0.02 ng/mL, inhibin B 10 pg/mL and testosterone below 0.45 nmol/L before and after hCG [23]. With preserved testicular function, AMH and inhibin B are normal and testosterone rises with hCG: in the other twin, testosterone rose from less than 0.45 to 13.28 nmol/L, with AMH above 23 ng/mL and inhibin B of 145 pg/mL [23]. In a girl with semilobar HPE, AMH at 12 weeks was 5.96 ng/mL (reference 39–91), testosterone 15 ng/dL and the response to hCG weak (530 ng/dL) [9]. In the newborn with PMDS of Voide and colleagues, minipuberty at 6 weeks was normal (testosterone 9.2 nmol/L, AMH 342.1 pmol/L, inhibin B 259 pg/mL), but AMH (149.8 pmol/L) and inhibin B (76 pg/mL) were below the reference ranges at 10 months [24]. Normal AMH, which in classic PMDS suggests an AMHR2 variant, does not exclude PPP1R12A [3].

5.3. Genetic testing

Karyotype or chromosomal microarray, with fluorescence in situ hybridisation (FISH) for SRY, is indicated in patients with external genital anomalies and in those with a female phenotype [2]. Microarray also detects the 12q21 deletion [4, 30]. GeneReviews describes two options: in the presence of distinctive findings, PPP1R12A sequencing followed by intragenic deletion/duplication analysis if negative, or a DSD or brain malformation panel including the gene; with a phenotype indistinguishable from other 46,XY DSD or brain malformations, exome or genome sequencing [2]. In practice, most published diagnoses resulted from exome or genome sequencing, often in trios [3, 9, 12, 23, 24].

These limitations have practical consequences. A negative exome does not exclude the syndrome: the patient of Bland and colleagues had a negative exome at 5 months and a negative reanalysis at 4 years, and the diagnosis came only at 11–12 years with trio genome sequencing followed by RNA sequencing, which showed partial retention of intron 17 [9]. The rearrangement in Picard's patient 4, with two sequences of 527 and 236 bp triplicated in tandem in the first non-coding exon, would not be detected by analysis limited to the coding regions [3]. Low-level mosaicism in the parents is not excluded by blood testing [2, 22]. In the absence of a point variant, a microarray should look for the 12q21 deletion [2].

The report should state the gene, the transcript with version (NM_002480.3), the Human Genome Variation Society (HGVS) nomenclature at c. and p. level, zygosity, origin (de novo confirmed with parentage testing, or presumed) and the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) class with the criteria applied [2, 15]. A variant is called de novo when it is not detected in the parents' DNA and maternity and paternity have been confirmed; without this test, it is «presumed de novo» [2]. The criteria used in the reports illustrate the classification: PVS1, PS2 and PM2 for de novo truncating variants; PVS1_Strong and PS3 after RNA studies for splicing variants [8, 9, 15, 24]. Some older variants were published on alternative transcripts (NM_001244990.2:c.1239+2T>G), which requires normalisation to the MANE transcript before comparison with databases [7, 13].

5.4. Algorithm

5.5. Prenatal and preimplantation diagnosis

When the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing are possible [2]. Without a family history, prenatal diagnosis results from investigation of ultrasound anomalies: the c.1239+2T>G variant was identified by trio exome sequencing on amniotic fluid at 24+5 weeks, after detection of a perineal mass at 24 weeks [13], and the first diagnosis of 12q21 deletion by array-CGH was made during pregnancy [4]. In a 12-week fetus with acrania, exencephaly and omphalocele, the diagnosis resulted from investigation after termination of pregnancy [12, 14].

6. Differential Diagnosis

6.1. Comparative table

6.2. Differential diagnosis of the urogenital form

In 46,XY DSD with undervirilisation, the classic differential between partial androgen insensitivity and partial gonadal dysgenesis is difficult because of clinical overlap, and many patients remain without an aetiological diagnosis [12]. In GUBS, the pointers are the coexistence of Müllerian derivatives with undervirilisation (which points to testicular dysgenesis and away from androgen insensitivity), extragenital malformations and de novo origin [12, 23]. The PMDS form is distinguished from PMDS due to AMH or AMHR2 by de novo dominant inheritance, by the association with digestive atresias, prematurity and, at times, cerebellar heterotopias or learning difficulties, and by normal AMH without AMHR2 variants; these malformations have never been described in PMDS due to AMH or AMHR2 [3]. In the Paris series, PPP1R12A accounted for 5 of 24 cases of PMDS without biallelic AMH or AMHR2 variants [3].

6.3. Differential diagnosis of the neurological form

In the presence of HPE or another midline malformation, the differential includes chromosomal causes (trisomy 13) and the other HPE genes [2, 11]. Smith-Lemli-Opitz syndrome shares HPE, ambiguous genitalia, toe syndactyly and polydactyly; measurement of 7-dehydrocholesterol, normal in the girl with semilobar HPE and polydactyly reported by Bland and colleagues, separates the two entities [2, 9]. Pseudotrisomy 13, a clinical designation for the association of HPE, severe facial anomalies, postaxial polydactyly and other malformations with a normal karyotype, is heterogeneous; OMIM allows for undetected microdeletions or de novo dominant variants in some cases, and the patient of Bland and colleagues, with semilobar HPE, bilateral postaxial polydactyly, ambiguous genitalia and a 46,XY karyotype, would have fitted that clinical picture before the molecular diagnosis [9, 34]. The combination of HPE or corpus callosum malformation with 46,XY DSD, intestinal atresia or Müllerian derivatives is the one that most strongly points to PPP1R12A [9, 12].

6.4. Differential diagnosis of intestinal atresia and perineal mass

In small intestinal atresia, about 20% of cases are associated with chromosomal anomalies and 15.2% with trisomy 21, according to the studies cited by Gomes and colleagues; the association with genital anomalies, Müllerian derivatives or imperforate anus justifies including PPP1R12A in genetic testing [3, 14]. The differential diagnosis of a fetal perineal mass includes anomalies of the external genitalia and sacrococcygeal teratoma; in a review cited by Chen and Tan, congenital perineal masses were associated with urogenital, anorectal or genital anomalies in 14 of 23 cases (60.9%) [13].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no cause-directed treatment and no specific clinical guideline for GUBS; the GeneReviews recommendations are expert opinion built on the published reports [2, 6]. Treatment is system-based and depends on each patient's phenotype, which ranges from a virilised adult with a residual uterus and normal intelligence to a child with HPE, epilepsy and a gastrostomy [3, 9]. For the DSD component, the general consensus statements (DSDnet, Endo-ERN) apply, and their recommendations are summarised below [33, 35]. The initial evaluation recommended by GeneReviews includes genital examination and karyotype, renal and pelvic ultrasound, hormonal studies during minipuberty, neurological assessment with brain MRI, developmental assessment, growth parameters, assessment of feeding and aspiration risk, ophthalmological and audiological assessment, a search for digital and joint anomalies, genetic counselling and assessment of family support needs [2].

7.2. Difference of sex development: team, information and sex assignment

GeneReviews recommends referral of 46,XY individuals with DSD to a multidisciplinary team of urology, endocrinology, genetics, gynaecology and psychology [2]. The 2018 DSDnet consensus advocates holistic care by multidisciplinary teams with peer support, transparent and progressive information throughout life, including information on fertility before adolescence, and recommends avoiding emotionally driven decisions and deferring non-urgent decisions, such as surgical ones, until psychological counselling has taken place; for irreversible procedures, such as genital surgery, it advises deferring intervention, whenever possible, until the person is old enough to take part in the decision [33].

Sex assignment in newborns with atypical genitalia is based on assessment of gonadal function and anatomy, in a decision shared with the parents. In the monozygotic twins of Tian and colleagues, the endocrinology, urology, gynaecology, psychology and genetics team assigned female sex to the twin without functional gonadal tissue and with markedly undervirilised genitalia, and male sex to the twin with functioning testes; at 3.5 years, the Pre-School Activities Inventory (PSAI) gave 55.95 points (neutral, slightly masculine) in the first and 84.55 (masculine) in the second [23]. The authors, in a country without legal recognition of a third gender, preferred assignment in early childhood; this position differs from that of the DSDnet consensus, which favours deferring irreversible interventions [23, 33]. In the patient of Bland and colleagues, the shared decision was to raise her as female, as the external genitalia were more compatible with that assignment [9]. GeneReviews recommends ensuring psychological support for those with gender identity questions [2].

7.3. Genital surgery and surgery of the Müllerian derivatives

GeneReviews recommends the usual treatment, by urology or gynaecology, of hypospadias, bifid scrotum, urogenital sinus anomalies and cryptorchidism in undervirilised 46,XY individuals [2]. The reports illustrate the options. In the twin raised as male, two-stage hypospadias repair, left orchidopexy and right herniorrhaphy were performed; in the twin raised as female, vaginoplasty and urethroplasty to separate the vagina from the urethra at 30 months [23]. In PPP1R12A-associated PMDS, Voide and colleagues planned, after laparoscopy at 3 years, a staged strategy of bilateral orchidopexy with incision of the Müllerian derivatives, preserving the gonadal blood supply and the vasa deferentia [24]; in one of Picard's patients, the Müllerian derivatives were removed together with the atretic right vas deferens, whereas the narrow left vas deferens was dissected from the uterine wall and preserved [3].

7.4. Gonads: tumour risk, gonadectomy and cryopreservation

GeneReviews recommends considering gonadectomy in individuals with dysgenetic gonads [2]. There are no germ cell tumour risk data specific to GUBS; in the reports read, the only tumour finding was a papillary cystadenoma of the epididymis in one of the twins [23]. The risk is extrapolated from 46,XY gonadal dysgenesis: according to the DSDnet consensus, it is much higher in gonadal dysgenesis, especially when it results from early defects of gonadal differentiation, than in disorders of androgen synthesis or action, and, in the absence of reliable tumour markers or imaging for precursor lesions, it is prudent to consider gonadal biopsies at the end of adolescence to exclude germ cell neoplasia in situ or gonadoblastoma in most individuals with 46,XY DSD who retain their gonads [33]. According to the same consensus, the risk is related to the degree of testicular differentiation of the gonad, assessed by histology and immunohistochemistry, and is modulated by age, gonadal location and, possibly, genetic predisposition; as the incidence of testicular germ cell tumours is concentrated in late adolescence and early adulthood, it is at that age that biopsies are most useful [33].

Testicular function may deteriorate after surgery. In one of Picard's patients with normal testosterone at 22 years, orchidopexy of a small inguinal testis was followed, six months later, by azoospermia and hypergonadotrophic testicular failure, and the ectopic contralateral testis was necrotic when it was removed [3].

7.5. Puberty induction and hormone replacement therapy

GeneReviews recommends the usual treatment of hormonal problems at and after puberty, including hormone replacement therapy, with referral to endocrinology [2]. There are no GUBS-specific doses; the following doses are those of the 2022 Endo-ERN guideline for congenital hypogonadism, including gonadal dysgenesis, an analogous condition in which these drugs are used for the same purpose [35]. Endo-ERN recommends that induction be conducted by a multidisciplinary team (R1.1); specialist assessment of girls with a condition at risk of hypogonadism from 8 years of age (R2.1); considering induction at around 11 years in most girls with gonadal dysgenesis without pubertal signs and with confirmed hypogonadism (R2.2, evidence ++OO); using 17β-oestradiol (R2.6, ++OO); monitoring every 3–6 months during induction (R2.7); adjusting the dose to progression (R2.8); adding progesterone after the first withdrawal bleed or after at least 2 years (R2.9); and switching to adult replacement at the end of induction (R2.10) [35]. In boys, it recommends pubertal assessment from 9 years of age in at-risk conditions (R3.2), induction in all those with permanent hypogonadism (R3.3), starting at around 12 years in high-risk diagnoses without pubertal signs (R3.4, +OOO) and testosterone as the induction drug (R3.5, ++OO) [35]. In boys with intellectual disability or behavioural problems, induction should be carried out in collaboration with mental health services, with information for carers on the effects of testosterone on impulsivity and adapted sex education (R3.3) [35].

Combined oral contraceptives containing ethinylestradiol should not be used to initiate puberty [35]. The Endo-ERN guideline acknowledges that not all formulations are available in every country and that brand names vary between countries; the oestrogens used for induction are adult preparations used off-label in children, and in many countries testosterone formulations are not licensed for pubertal induction, so the choice also depends on local availability [35]. In individuals with functioning testes, such as Picard's patients with spontaneous puberty, induction is not necessary, but gonadal function should be monitored [3, 35].

7.6. Gastrointestinal tract, feeding and nutrition

Intestinal and oesophageal atresias, imperforate anus and omphalocele are treated surgically in the first days of life; in the reports, resection of the atretic segment with double jejunostomy or primary anastomosis, prolonged parenteral nutrition and restoration of continuity between 8 weeks and 3 months allowed an uncomplicated course in several patients, with 110 cm of residual small intestine in one of them [3, 21]. A boy operated on the second day remained free of digestive symptoms related to the atresia, with functional constipation, and without specific surveillance for surgical complications [21]. GeneReviews recommends the usual surgical and gastroenterological treatment of intestinal atresia, structural assessment if there are signs of obstruction, feeding therapy, gastrostomy for persistent feeding difficulties or faltering growth, a low threshold for clinical swallowing assessment or radiological study if there are signs of dysphagia or aspiration pneumonia, and stool softeners, prokinetics, osmotic laxatives or other laxatives for constipation [2]. Foods may be thickened or chilled for safety, and a nasogastric tube or gastrostomy becomes necessary when dysfunction is severe [2].

7.7. Nervous system, development and rehabilitation

Epilepsy is treated with antiepileptic drugs chosen by an experienced neurologist; many may be effective, and none has been shown to be specifically effective in this disease [2]. In the newborn girl with seizures on the second day, phenobarbital and midazolam reduced seizure frequency [8]. Parents and carers should be educated about the presentations of seizures [2]. GeneReviews recommends early intervention from 0 to 3 years (occupational therapy, physiotherapy, speech and feeding therapy), special education with an individual plan, physiotherapy to reduce the risk of contractures, scoliosis and hip dislocation, assistive devices, occupational therapy for fine motor skills, augmentative and alternative communication when expressive language is limited, behavioural interventions of the type used in autism spectrum disorder and, when necessary, pharmacological treatment of ADHD guided by a developmental paediatrician [2]. In hypertonia or dystonia, the decision on baclofen, tizanidine, botulinum toxin, antiparkinsonian drugs or orthopaedic surgery rests with the specialists involved [2].

7.8. Growth and growth hormone

In the boy of Saul and colleagues with growth hormone deficiency and ectopic posterior pituitary, somatropin was started at 0.8 mg/day (0.25 mg/kg/week), at the upper end of the prepubertal dose in the Pediatric Endocrine Society recommendations cited by the authors; IGF-1 remained normal and growth velocity rose to 7.5–7.8 cm/year, with a height of 131 cm (3.57th centile) at 11 years [21]. This is an isolated report; the indication and dose follow the general rules for growth hormone deficiency, with no GUBS-specific data. The authors recommend early endocrine referral for patients with PPP1R12A variants and short stature [21].

7.9. Kidney, eyes, hearing and skeleton

Renal anomalies are managed by nephrology and urology; vision and strabismus by ophthalmology, with visual support services in early intervention or at school; hearing loss by audiology; and kyphoscoliosis and contractures by orthopaedics [2]. In the patient with profound deafness and a common cochleovestibular cavity, bilateral cochlear implants at 18 months, after a trial with hearing aids, had a good outcome [15].

7.10. Family, palliative care and transition

GeneReviews recommends involving social services to link families with local resources, respite care and support, coordinating the multiple appointments, equipment and medications, reassessing the need for palliative care or home nursing, and considering adapted sport [2]. Transition to adult care, for the DSD component, should involve the adult specialist early and an open discussion of all clinical information, including information that was not fully shared during childhood [33]. The patient of Bland and colleagues was lost to genetic follow-up between 4 and 11 years and was diagnosed only after an admission for malnutrition, which shows the need for continued follow-up and genetic reanalysis [9].

7.11. Special situations

Agents to avoid. The sources consulted do not identify drugs specifically contraindicated in GUBS [2]. Pregnancy. No pregnancies have been published in women with GUBS; the DSDnet consensus mentions successful pregnancies after oocyte donation in women with 46,XY DSD and a uterus, in numbers too small to draw conclusions on indications and success rates [33]. Perioperative care. Feeding difficulties, aspiration risk and epilepsy in patients with brain malformation should be taken into account in anaesthesia; the sources do not describe anaesthetic risks specific to the syndrome [2]. Fertility. Fertility is reduced in almost all DSD; azoospermia was documented in a patient with PPP1R12A-associated PMDS, and the DSDnet consensus mentions microdissection testicular sperm extraction as an option for some men without sperm in the ejaculate, provided that testicular biopsy shows sperm [3, 33].

7.12. Regulatory status and clinical trials

There are no interventional clinical trials in GUBS, so there is no table of trials with outcomes, confidence intervals or absolute rates to present. A negative search in one registry does not prove the absence of studies in other registries or in preparation.

7.13. Developments in the last 12 months (November 2025 to October 2026)

The literature and the trial registry consulted do not mention opinions, marketing authorisation applications or regulatory authorisations related to GUBS in this period.

7.14. Guideline recommendations and divergences

The main divergence concerns surgery and the gonads: GeneReviews, written for the syndrome, recommends considering gonadectomy for dysgenetic gonads without setting the timing, whereas the DSDnet consensus favours preservation with biopsy at the end of adolescence and deferral of irreversible interventions [2, 33]. In the practice described in the reports, sex assignment and genital surgery took place in early childhood, in line with the preferences of the teams and families [9, 23]. Other national guidelines differ on the timing of gonadectomy.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

Genetic testing of the parents is indicated to confirm de novo origin and to allow reliable counselling [2]. Parental mosaicism has not yet been described in GUBS, but leucocyte testing does not detect exclusively germline mosaicism or all somatic mosaicism [2, 22]. In the monozygotic twins with the same variant, the phenotypic discordance shows that the recurrence risk does not allow severity to be predicted [23]. The maternal and paternal families of the patient of Voide and colleagues included cases of cryptorchidism, with no information allowing them to be related to the variant, which was de novo in the proband [24]; in one of Picard's families, a previous pregnancy had ended with a non-surviving male fetus at 25 weeks, without autopsy [3].

8.2. Transmission by the affected person

The probability of transmission from an affected person is 50% in each pregnancy [2]. In practice, transmission is limited by fertility: 46,XY individuals with gonadal dysgenesis have no gametes, and in PPP1R12A-associated PMDS azoospermia with testicular failure has been documented [3, 23]. The variable expressivity, with virilised patients of normal intelligence, implies that a person with a mild phenotype could, in theory, transmit the variant to a child with a severe phenotype [3, 23]; as of October 2026 no familial transmission had been published.

8.3. Prenatal and preimplantation diagnosis

The ideal time to discuss the risk and the options for prenatal and preimplantation diagnosis is before pregnancy [2]. Despite the low risk (about 1%) in de novo cases, prenatal diagnosis and preimplantation testing may be considered, and views on the use of prenatal diagnosis vary between professionals and within families [2]. The anomaly scan and, if indicated, fetal MRI allow detection of HPE, acrania, intestinal atresia and perineal masses, as in the fetal reports [12, 13, 21].

8.4. Counselling of minors and communication

The DSDnet consensus recommends that children be informed early and progressively about their condition, including fertility before adolescence [33]. Genetic counselling should be provided by genetics professionals and address the nature of the syndrome, its inheritance and the implications for medical and personal decisions [2]. When the proband's variant is de novo and the parents test negative, the residual risk for siblings is that of germline mosaicism, estimated at about 1% [2].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

The prevalence of GUBS has not been determined [2]. The published counts measure only reported cases: 12 individuals in 2020, 13 in 2024, 20 in 2025, 22 and 23 in the 2025–2026 reviews and 24 pathogenic or likely pathogenic variants compiled in July 2026 [8, 9, 12, 14, 15, 23]. Adding up the reports read up to October 2026, there are about 30 individuals with point or intragenic variants, not including the 12q21 deletions; this number is not a prevalence estimate. Detection depends on access to exome or genome sequencing, and patients with a mild phenotype, 46,XX women without malformations and PMDS with complete virilisation are probably under-represented [3, 9, 23].

Two proportions give an idea of the relative weight of the gene in selected populations. In the HPE cohort of the founding series, 2 of 277 patients without variants in the four main genes had a PPP1R12A variant, and in the DSD cohort of 94 families 2 patients were found [12]. In the Paris PMDS series, PPP1R12A accounted for 5 of 24 cases (21%) without biallelic AMH or AMHR2 variants, which in turn represent about 10–12% of PMDS [3]. These proportions refer to referral cohorts and not to the general population. HPE as a whole occurs in about 1 in 10,000 live births and 1 in 250 conceptions, according to the figures cited in the founding article [12].

9.2. Geographical and population distribution

The published patients come from the United States (including patients of Hispanic origin) and Canada, Europe (Germany, France, the Netherlands, Italy, Switzerland), China and Mexico [3, 8, 9, 12, 15, 21–24, 26, 27]. One of Picard's patients had a French mother and a Moroccan father, and the patient of Voide and colleagues had parents of Moroccan and Kurdish origin [3, 24]. No founder variants or population recurrence have been described; the only repeated variant, c.3092A>T, arose de novo in two unrelated patients, one 46,XY and the other 46,XX [14, 28]. The sources consulted contain no data from Portugal or Brazil, which does not mean that there are no patients in those countries.

9.3. Special populations

Preterm infants. Prematurity is frequent in the reports (all five of Picard's patients and eight of 22 in one review), and neonatal respiratory and digestive complications determine the early course [3, 9, 14]. 46,XX individuals. Data are scarce, with phenotypes ranging from anencephaly to the absence of genital anomalies [8, 12–14]. Adults. The form with complete virilisation may be diagnosed in adulthood, with a risk of loss of testicular function and infertility [3]. People with intellectual disability. Puberty induction and sex education require adaptation, according to the Endo-ERN guideline [35].

9.4. Reference networks and patient associations

In Europe, the DSD and puberty induction component is covered by Endo-ERN, congenital malformations and intellectual disability by ERN ITHACA, urogenital anomalies by ERN eUROGEN, digestive atresias by ERNICA and epilepsy by ERN EpiCARE [16–20]. GeneReviews lists as resources NHGRI (Learning About Holoprosencephaly), Accord Alliance, Families for HoPE, GARD, INCIID, NINDS and NORD, mainly for HPE and DSD [2]. The dsdfamilies association supports families of children with DSD, and Families for HoPE supports families of children with HPE [37, 38]. There is no GUBS-specific patient association in the sources consulted.

10. Illustrative Clinical Case

10.1. 46,XY monozygotic twins with the same variant and different assigned sexes

Tian and colleagues, from the Children's Hospital of Zhejiang University (Hangzhou, China), described two 46,XY monozygotic twins, spontaneously conceived and born by caesarean section at 37 weeks after an uncomplicated pregnancy, with no family history of malformations, who were seen in May 2022, at 10 months, for ambiguous genitalia; both had been raised as male [23]. Twin A had Prader stage III genitalia, with an EMS of 0, a small clitoris-like phallus, a single urogenital sinus opening on the perineum and impalpable gonads; twin B had Prader stage IV, an EMS of 5.5, severe hypospadias that had already undergone a first-stage repair, left cryptorchidism and a right hernia, with testis-like masses in the left inguinal region and right scrotum [23]. Photographs of the genitalia at 10 and 30 months are in figure 1 of the article (figure 1) [23].

In twin A, LH was 26.23 IU/L and FSH 140.22 IU/L, testosterone below 0.45 nmol/L before and after hCG stimulation, AMH 0.02 ng/mL and inhibin B 10 pg/mL; in twin B, gonadotrophins were normal, testosterone rose from less than 0.45 to 13.28 nmol/L with hCG, and AMH (above 23 ng/mL) and inhibin B (145 pg/mL) were normal for age [23]. Ultrasound showed a prepubertal uterus in both (1.6 × 0.9 × 0.6 cm in twin A; 2.7 × 1.2 × 0.7 cm in twin B) and gonads only in twin B; brain MRI showed mild enlargement of the lateral ventricles in both [23]. On urethroscopy, the urethra and vagina joined in a single channel with a visible cervix; at laparoscopy there was a uterus in both, epididymis-like tissue without gonads in twin A, confirmed by histology, and testes without epididymis or vas deferens in twin B, with a papillary cystadenoma of the epididymis resected (figure 3) [23]. Exome sequencing identified in both the de novo variant NM_002480.3:c.1551-2A>G, at the canonical acceptor of intron 11, classified as pathogenic [7, 23].

In a decision shared between the multidisciplinary team and the parents, twin A, without functional gonadal tissue and with markedly undervirilised genitalia, was thereafter raised as female and underwent vaginoplasty and urethroplasty at 30 months, with an anticipated need for hormone replacement from puberty; twin B, with functioning testes, remained male and underwent the second stage of hypospadias repair, left orchidopexy and right herniorrhaphy (figure 5) [23]. At 3.5 years, the PSAI classified the gender role behaviour of twin A as neutral, slightly masculine (55.95), and that of twin B as masculine (84.55); follow-up is ongoing [23].

10.2. Interpretation of the case

The case shows three aspects of the syndrome. First, the same variant, on an identical genetic background, produced gonadal dysgenesis with almost undetectable AMH in one twin and functioning testes with a uterus in the other, which separates failure of Müllerian regression from gonadal failure and confirms the variable expressivity [3, 23]. Second, the hormonal profile with hCG and the laparoscopy were decisive for sex assignment and the surgical plan [23]. Third, feminising genital surgery at 30 months and assignment in early childhood reflect local practice and the country's legislation; the DSDnet consensus recommends deferring irreversible interventions, whenever possible, until the person can take part in the decision, and the psychosexual outcome will only be known with follow-up into adulthood [23, 33]. The papillary cystadenoma of the epididymis is not a germ cell tumour, and management of twin B's gonads and twin A's gonadal remnants follows the recommendations for gonadal dysgenesis [23, 33].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

There are no survival or long-term natural history studies, and the prognosis depends on the organ affected [2]. The forms with severe brain malformation have the worst prognosis: anencephaly is lethal, and HPE is associated with moderate to profound intellectual disability, epilepsy and feeding difficulties [2, 12]. A girl with semilobar HPE had, at 11 years, global delay, epilepsy, spastic tetraparesis, a gastrostomy and severe malnutrition [9]. In the forms without brain malformation, development may be normal or mildly delayed: two patients with HPE in the founding series reached 15 years, a 46,XY woman with streak gonads was 45 years old with no other anomalies, and patients with PMDS reached adulthood with normal physical and mental health and university studies [3, 12]. One of Picard's five patients was stillborn, with intestinal atresia and cerebellar heterotopias [3].

The gonadal prognosis depends on each situation: without functioning gonads there is infertility and a need for hormone replacement; with functioning testes there may be spontaneous puberty, but testicular function may deteriorate, as shown by the fall in AMH and inhibin B in the first year of a newborn and by testicular failure in an adult after orchidopexy [3, 23, 24]. Patients operated on for intestinal atresia progressed, in the reports, without late digestive complications [3, 21]. Profound deafness with inner ear malformation had a good outcome with cochlear implants [15].

11.2. Surveillance

GeneReviews recommends that people with DSD be followed by an interdisciplinary team of endocrinology, genetics, obstetrics and gynaecology, psychology and urology [2]. Surveillance of retained gonads is an extrapolation from 46,XY gonadal dysgenesis, because there are no GUBS-specific tumour risk data; the DSDnet consensus notes that there are no reliable tumour markers or imaging techniques for early detection of precursor lesions [33].

12. Summary and Final Considerations

GUBS is an autosomal dominant congenital malformation syndrome caused by heterozygous, almost always de novo, loss of function of PPP1R12A, the gene for the MYPT1 subunit of myosin phosphatase, which is intolerant of loss of function. Since the description of 12 patients in 2020, about 30 individuals with point or intragenic variants have been published, with genitourinary anomalies in about four fifths, brain malformations in some of those assessed, developmental delay in nearly half and digestive atresias in a minority. The genital spectrum ranges from hypospadias to complete gonadal dysgenesis with female genitalia and includes persistence of Müllerian derivatives with complete external virilisation and normal AMH; the neurological spectrum ranges from normal intelligence to HPE and anencephaly. Reports from 2025–2026 added neonatal epilepsy, growth hormone deficiency, deafness with inner ear malformation, polydactyly, optic nerve hypoplasia and a 46,XX fetal perineal mass.

The diagnosis is molecular: karyotype or microarray with SRY and exome or genome sequencing, with RNA studies for intronic variants and microarray for the 12q21 deletion, bearing in mind that a negative exome does not exclude the syndrome. Treatment is system-based and, for the DSD component, follows the general consensus statements: multidisciplinary team, progressive information, irreversible decisions deferred whenever possible, assessment of gonadal function during minipuberty and puberty, management of the tumour risk of dysgenetic gonads and puberty induction with oestradiol or testosterone according to the Endo-ERN guideline. The divergences between sources concern the timing of gonadectomy and genital surgery. The recurrence risk for siblings is about 1% when the variant is de novo, and 50% for the children of an affected person, although fertility is reduced. Expressivity is variable even between monozygotic twins, there are no genotype-phenotype correlations or prevalence data, and the sources consulted contain no data from Portugal or Brazil.

13. References

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