Alternative titles; symbols
SNOMEDCT: 718680001; ORPHA: 141007; DO: 0060382; MONDO: 0009795;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q22.31 | Orofaciodigital syndrome IX | 258865 | Autosomal recessive | 3 | TBC1D32 | 615867 |
A number sign (#) is used with this entry because of evidence that orofaciodigital syndrome IX (OFD9) is caused by homozygous or compound heterozygous mutation in the TBC1D32 gene (615867) on chromosome 6q22.
Orofaciodigital syndrome IX (OFD9) is an autosomal recessive disorder characterized by severe but highly variable expression of midline defects, including abnormal pituitary development resulting in variable pituitary hormone deficiencies. Common facial dysmorphisms include frontal bossing and hypertelorism, and variable eye defects have been observed, including microphthalmia, coloboma, and retinal dystrophy. Psychomotor development is also highly variable, ranging from normal to severely delayed (Adly et al., 2014; Hietamaki et al., 2020; Ahn et al., 2021).
Gurrieri et al. (1992) described 2 brothers with an orofaciodigital syndrome which did not seem to fit into any of the 7 previously described types (Toriello, 1988; Munke et al., 1990). The 2 brothers were mildly mentally retarded. Both showed a small notch in the upper lip. The older brother had a highly arched palate with bifid tongue and a supernumerary lower canine bilaterally. The younger brother had a lobulated, hamartomatous tongue, and multiple frenula. The specific retinal abnormalities in the brothers reported by Gurrieri et al. (1992) were retinochoroidal lacunae of colobomatous type, similar to those seen in Aicardi syndrome (304050).
Nevin et al. (1994) reported a female case of OFDS with component manifestations typical of type II (252100), namely median cleft of the upper lip, multiple oral frenula, and lobulated or hamartomatous tongue, associated with retinal abnormalities as distinguishing feature. They referred to the disorder as OFDS type IX.
Sigaudy et al. (1996) reported the case of a 6-month-old girl with OFD anomalies associated with areas of chorioretinal atrophy. The parents were nonconsanguineous; the maternal and paternal ages at her birth were 33 and 41 years, respectively. She showed multiple hamartomas of the oral cavity, lobulated tongue, alveolar frenula, and a small median cleft of the upper lip. The great toes were broad. Psychomotor development was delayed. CT scan showed atrophy of the frontal and parietal lobes and NMR showed a hypothalamic hamartoma.
Nagai et al. (1998) described an affected female with features consistent with OFDS IX who was also noted to have Dandy-Walker malformation and retrobulbar cysts.
Erickson and Bodensteiner (2007) described 2 pairs of sibs (2 females, and 1 female and 1 male) from the Navajo population with orofaciodigital syndrome. In addition to retinal colobomas and mild digital anomalies, the sibs also had severe microcephaly, mental retardation, and short stature. Erickson and Bodensteiner (2007) suggested that this condition is a variant of OFDS IX caused by a unique allele of increased frequency in the Navajo population.
Adly et al. (2014) reported a Saudi male infant (index 1) who died at age 6 months with a severe ciliopathy phenotype and mutation in the TBC1D32 gene. The proband was identified antenatally at 24 weeks' gestation to have cleft lip, abnormal hands, and small head circumference. At birth, he was noted to have microcephaly, right microphthalmia, left anophthalmia, bilateral optic disc coloboma, severe midline cleft involving the lip and alveolus, hypertelorism, severe choanal stenosis, left-hand postaxial polydactyly, and ambiguous genitalia, as well as patent ductus arteriosus (PDA) and atrial septal defect (ASD). He later developed panhypopituitarism secondary to absent pituitary gland as confirmed by brain MRI, which also showed partial agenesis of the corpus callosum and agenesis of the inferior cerebellar vermis. Abdominal and renal ultrasounds were normal. In the neonatal period, he developed tonic-clonic seizures, and electroencephalogram (EEG) showed focal discharge from the right parietotemporal area. He died of cardiac arrest at 6 months of age due to severe electrolyte imbalance. Adly et al. (2014) considered the severe ciliopathy phenotype of this patient to best fit OFD type IX in view of the prominent eye involvement, although the patient lacked the classic tongue anomalies.
Hietamaki et al. (2020) reported a Finnish brother (I.3) and sister (I.5) and a Pakistani girl (II.8) who had pituitary hormone deficiencies with features of OFD and mutation in the TBC1D32 gene. The Finnish boy, who was born with micropenis and bilateral cryptorchidism, had growth hormone (GH1; 139250), adrenocorticotropin (ACTH), thyroid-stimulating hormone (TSH; see 188540), and gonadotropin deficiencies. On brain MRI, the sella turcica and hypophysis were not identifiable, and an ectopic neurohypophysis was present near the tuber cinereum. He had a prominent forehead and low-set, posteriorly rotated ears. He also had communicating hydrocephalus and developmental delay, and was partially dependent on nasogastric tube feeding until 5 months of age. At age 3 years, he died unexpectedly following an infection, despite adequate hydrocortisone supplementation. His 10-year-old sister was hypotonic at birth, with hypoglycemia and metabolic acidosis, and was found to have GH and TSH deficiencies. Brain MRI showed absent sella turcica and anterior pituitary gland, with putative neurohypophyseal tissue detected near the tuber cinereum. She experienced progressive retinal dystrophy, motor delay, and neuromuscular scoliosis, and exhibited leg-length discrepancy. Her upper jaw was narrow with misaligned teeth, and she had feeding difficulties. Examination at age 8 years showed dysmorphic craniofacial features, including a prominent forehead, wide nasal bridge, short upturned nose, hypertelorism, downward-slanting palpebral fissures, posteriorly rotated ears, low hairline, and nuchal hair. She had a barrel-like chest with widely spaced nipples, and hypermobility in the upper limbs, with prominent finger pads, fingernail clubbing, slight 2-3 syndactyly of the toes, and bilateral sandal gap. She had normal cognitive development. In the Pakistani family, the proband was born with distinctive facial features, including broad and prominent forehead, wide anterior fontanel, hypertelorism, low-set ears, flat nasal bridge, anteverted nares, left-sided choanal atresia, slight midline groove of the tongue, serrated gums, ankyloglossia, and high narrow palate. She had small hands, with postaxial polydactyly of the left hand. Brain MRI showed partial agenesis of the corpus callosum, small anterior pituitary gland, and small optic chiasm, as well as dysplasia of the cerebellar vermis with midline cleft and small brainstem. Her GH levels were low, with normal cortisol; she responded well to GH replacement therapy, although her height was still below the 3rd centile at age 4.75 years. At age 5.5 years, she had global developmental delay, no speech, and could not stand without support. She exhibited bilateral divergent squint and severe cerebral visual impairment with reduced visual acuity but showed normal retinal responses on electroretinography. A second pregnancy in the family was terminated after prenatal scan showed midline facial clefting and femoral length below the 3rd centile; postmortem showed a female fetus with midline cleft lip and partial intestinal malrotation. All 3 affected children required tympanostomy tubes due to chronic middle ear infections.
Ahn et al. (2021) reported a 6-year-old Korean boy who had panhypopituitarism and respiratory insufficiency with other anomalies, and mutation in the TBC1D32 gene. He required immediate intubation at birth and long-term respiratory support with tracheostomy, as well as a feeding tube for nutritional support. He exhibited dysmorphic facies, with prominent forehead, hypertelorism, choanal atresia, bilateral ptosis, and strabismus. He had ambiguous genitalia, bilateral cryptorchidism, and perineal ectopic anus, and showed relatively short limbs. Brain MRI showed partial agenesis of the corpus callosum and no visible pituitary stalk. He developed hydrocephalus requiring ventriculoperitoneal shunt. Developmental milestones were markedly delayed, and at 6 years of age, he could sit up and point to objects, but had no speech. Lee et al. (2024) provided follow-up on the Korean boy (designated patient 2) reported by Ahn et al. (2021) at age 8 years. His hormone deficiencies included GH, TSH, ACTH, and antidiuretic hormone (ADH; see 192340). Despite hormone replacement therapy, he had marked short stature.
Harris et al. (2023) reported 3 unrelated children (probands 1, 2, and 7) with orofaciodigital anomalies and mutation in the TBC1D32 gene. Proband 1 was a 3-month-old girl with microcephaly, brachycephaly, and mildly dysmorphic facial features, including deep-set eyes, prominent nose, long philtrum, and thin upper lip. She had 2-3 toe syndactyly, increased muscle tone, mild joint restriction, and developmental delay. Brain imaging revealed ventriculomegaly, small cerebellum with hypoplasia of the inferior vermis, and multiple skull deformities, including asymmetric flattening of the right posterior parietal bone and bilateral hypoplasia of the frontal bones. Proband 2 was a 3-month-old girl with global developmental delay who exhibited relative macrocephaly with prominent forehead, midface hypoplasia, single median incisor, choanal stenosis, ptosis, strabismus, short limbs, and brachydactyly. Brain MRI showed an apparent ectopic pituitary, and she had GH and TSH deficiencies. Proband 7 was a 10-year-old Brazilian girl with microcephaly, short stature, and intellectual disability. She had deep-set eyes, ptosis, blue sclerae, full lips, and pectus excavatum. Skeletal survey revealed nonspecific shortening of the long bones and bilateral absence of distal phalanges of the fifth toes. Brain MRI was normal.
Garcia-Bohorquez et al. (2025) reported a 12-year-old Spanish boy who had OFD9 with anomalies of the pituitary gland, sensorineural hearing loss, retinal dystrophy, and mutation in the TBC1D32 gene. The proband exhibited craniofacial dysmorphisms, including prominent forehead, hypertelorism, low nasal bridge with broad root and tip, and low-set ears. He had hamartomatous lesions on the inner surface of the lip and a sublingual frenulum. Skeletal anomalies included short stature, narrow chest and clavicles with shoulder anteversion, brachydactyly of the hands and feet, and fifth-finger clinodactyly. He had learning difficulties and was diagnosed with attention-deficit/hyperactivity disorder at age 8 years. He experienced sensorineural hearing loss, which had a transmissive component due to secretory otitis media. He was also diagnosed with retinopathy at age 12. Brain MRI showed complete absence of the septum pellucidum, midline fusion of the fornices, abnormal sulcation of both hippocampi, hypoplastic sella turcica, and ectopic neurohypophysis. Hormone analysis was not reported.
Based on their report of affected males, Gurrieri et al. (1992) recognized that inheritance of OFDS IX might be either autosomal or X-linked recessive.
Nevin et al. (1994) suggested that OFDS IX is inherited in an autosomal recessive manner since their reported patient was female.
Erickson and Bodensteiner (2007) also supported autosomal recessive inheritance based on the finding of the disorder in sibs from the Navajo population, which has undergone several genetic 'bottlenecks.'
The transmission pattern of OFD9 in the families reported by Hietamaki et al. (2020) was consistent with autosomal recessive inheritance.
In a Saudi male infant who died at age 6 months with a severe ciliopathy phenotype featuring midline cleft, microcephaly, and colobomatous microphthalmia/anophthalmia, Adly et al. (2014) identified homozygosity for a splice site mutation in the TBC1D32 gene (615867.0001). Familial segregation was not reported, but the mutation was not found in Saudi controls or in public variant databases.
In 2 Finnish sibs (I.3 and I.5) with pituitary gland and OFD anomalies, 1 of whom also exhibited progressive retinal dystrophy, Hietamaki et al. (2020) identified compound heterozygosity for mutations in the TBC1D32 gene: a 2-bp duplication (258865.0010) and a 1-bp deletion (258865.0011). Their unaffected parents were each heterozygous for 1 of the variants, as was a healthy brother. The 1-bp deletion was not found in public variant databases, whereas the 2-bp duplication was present in the gnomAD database at low minor allele frequency. In a Pakistani girl (II.8) with developmental delay, features of OFD syndrome, and GH deficiency, the authors identified homozygosity for the previously reported TBC1D32 splice site mutation (615867.0001). Sanger sequencing confirmed the mutation in the proband and in an affected fetus in the family, and the carrier status of the unaffected parents.
Hietamaki et al. (2022) reported a Finnish boy with pituitary stalk interruption syndrome, resulting in GH, ACTH, TSH, and gonadotropin deficiencies. Limited clinical information was provided, but obstructive hydrocephalus and anomalies of the midbrain, hippocampus, pons, cerebellar vermis, and Sylvian fissure were tabulated, as well as bilateral ptosis, anisocoria, and ocular colobomas. He also had micropenis, cryptorchidism, and anteriorly placed anus, and was reported to have von Willebrand disease (see 193400). The patient was heterozygous for a 2-bp insertion (c.1166_1167insGT; 258865.0010) predicted to result in frameshift and premature termination. The insertion was present in gnomAD at low minor allele frequency, and ACMG classification was listed as 'uncertain significance'.
By whole-exome sequencing in a 6-year-old Korean boy with panhypopituitarism and craniofacial anomalies, Ahn et al. (2021) identified compound heterozygosity for a nonsense substitution (R734X; 615867.0012) and a splice site mutation (615867.0013) in the TBC1D32 gene. His unaffected parents were each heterozygous for 1 of the variants, neither of which was found in public variant databases.
In 3 unrelated children (probands 1, 2, and 7) with orofaciodigital anomalies, 1 of whom also had an ectopic pituitary gland with GH and TSH deficiencies, Harris et al. (2023) identified biallelic mutations in the TBC1D32 gene. Proband 1 was compound heterozygous for N712D and G1061A substitutions, proband 2 was compound heterozygous for a splice site mutation (c.2481+4A-T) and a Y1191C substitution, and proband 7 was homozygous for an H1176R substitution. All missense variants but Y1191C were considered to be variants of unknown significance; minigene assay showed skipping of exon 21 with the splice site variant. Parental segregation was reported for proband 1, with both unaffected parents being heterozygous for 1 of the missense variants.
In a 12-year-old Spanish boy who had orofaciodigital anomalies with hypoplastic sella turcica and ectopic neurohypophysis, sensorineural hearing loss, and retinal dystrophy, who was negative for mutation in known retinal dystrophy- and hearing loss-associated genes, Garcia-Bohorquez et al. (2025) identified compound heterozygosity for a 1-bp deletion (615867.0014) and a splice site mutation (615867.0015) in the TBC1D32 gene. His unaffected parents were each heterozygous for 1 of the variants.
Associations Pending Confirmation
For discussion of a possible association between variation in the SCLT1 gene and orofaciodigital syndrome IX, see 611399.0001.
In Bromi-mutant mice, Ko et al. (2010) identified a recessive splice-site mutation in mouse Tbc1d32 (615867), which they called Bromi. Bromi-mutant mice exhibit exencephaly with absence of cephalic ventral midline furrow, poorly developed eyes, and preaxial polydactyly. Scanning electron microscopy revealed that Bromi-mutant neuroepithelium showed curled axonemes surrounded by dilated ciliary membranes. Morpholino-mediated knockdown of bromi in zebrafish resulted in a similar phenotype, with curvature of the body axis, hydrocephalus, and pronounced curling of cilia in distal kidney tubules. Compared with Bromi-mutant mice, ciliary defects were more pronounced in bromi-knockdown zebrafish, whose kidney tubules showed ciliary membranes that were detached from axonemes along 1 side only, with dramatic expansion within the kidney tubule lumen. In culture, Bromi-mutant mouse neural progenitors responded to low and intermediate levels of Shh, but not to a high level of Shh. Bromi-mutant neurons showed reduced activation of Shh downstream regulators Gli2 (165230) and Gli3 (165240). Bromi-mutant embryos and fibroblasts exhibited significantly reduced Ccrk protein levels compared with controls. Ko et al. (2010) concluded that BROMI and CCRK coordinate assembly of the axoneme and ciliary membrane, allowing GLI proteins to be properly activated in response to SHH signaling.
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