Alternative titles; symbols
SNOMEDCT: 763774001; ORPHA: 2662; DO: 0111842;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq26.2 | Keipert syndrome | 301026 | X-linked recessive | 3 | GPC4 | 300168 |
A number sign (#) is used with this entry because of evidence that Keipert syndrome (KPTS) is caused by hemizygous mutation in the GPC4 gene (300168) on chromosome Xq26.
Keipert syndrome (KPTS) is characterized by craniofacial and digital abnormalities and variable learning difficulties. The distinctive facial appearance includes broad forehead, hypertelorism, prominent nose, wide mouth, and prominent upper lip with cupid bow configuration. Digital anomalies are also distinctive, with widening of all distal phalanges, particularly of the thumbs and great toes (Amor et al., 2019).
Keipert et al. (1973) described 2 brothers with a syndrome of sensorineural deafness, abnormal facies (especially nose), and broad thumbs. The nasal bridge was high and broad. The upper lip was protuberant with a striking cupid bow conformation. All distal phalanges were broad except for those of the fifth fingers, which showed clinodactyly. Balci and Dagli (1996) described 2 brothers from Turkey with this syndrome. At ages 17 and 21 years, they showed depressed nasal bridge, prominent frontal bones (especially supraciliary ridges), hypoplastic maxilla, mild sensorineural hearing loss, broad phalanges, and mild pulmonic stenosis. The systolic gradient at the pulmonic valve was 50 mm Hg. Both brothers had a complaint of dyspnea and both showed on laryngoscopy short, floppy, and edematous vocal cords and an omega-shaped epiglottis. Inheritance was thought to be autosomal or X-linked recessive. Balci and Dagli (1996) reported pulmonic stenosis and hoarseness as additional features.
Reardon and Hall (2003) described a 7.5-year-old boy with clinical, radiologic, and audiologic features consistent with Keipert syndrome. The defining features appeared to be deafness associated with brachydactyly and broad thumbs and halluces.
Amor et al. (2007) described Keipert syndrome in the nephew of the 2 brothers originally described by Keipert et al. (1973); the nephew was the son of an unaffected sister. Pregnancy was normal with the exception of the detection of unilateral renal agenesis on antenatal ultrasound. He was assessed at 7 months and was found to have facial and digital findings similar to his maternal uncles. Audiology showed moderate bilateral sensorineural hearing loss. The mother was examined and exhibited no manifestations of the disorder.
Nik-Zainal et al. (2008) reported 2 unrelated individuals with possible Keipert syndrome. One was a 43-year-old man investigated for infertility. He had short stature and characteristic facial features, including flattening of the nasal tip, depressed nasal bridge, prominent supraorbital ridge, hypertelorism, and maxillary retraction. He also had brachydactyly with broad great toes and thumbs. Radiographic studies showed shortening of the distal phalanges of all fingers and thumbs except for the fifth fingers. The distal phalanges were short and broad with prominent tufts. He had moderate sensorineural hearing loss. The second patient was a 2-year-old boy with facial dysmorphic features and marked brachytelephalangism of the hands. Radiographic studies showed shortening of the distal phalanges associated with abnormal epiphyses.
Derbent et al. (2011) described a 14-year-old boy with the classic findings of Keipert syndrome as well as isolated fibrous dysplasia of the sphenoid sinus. The patient had previously undergone surgery for peripheral pulmonary artery stenosis, and was referred for evaluation of unusual facies, hearing loss, and headaches. Examination revealed hypertelorism, underdeveloped maxilla, high nasal bridge, depressed nasal ridge, short columella, exaggerated cupid bow upper lip vermilion, high and narrow palate, retrognathia, and low-set and posteriorly rotated ears. His fingers and toes were short, with broad thumbs and halluces, and he had long second toes. Radiographs showed short terminal phalanges of fingers and toes, and broad thumbs and halluces with large epiphyses. CT of the head to evaluate the headaches revealed an expansive sclerotic lesion filling the sphenoid bone, with heterogeneous ossification that displayed a 'ground glass' appearance characteristic of fibrous dysplasia. A hearing test demonstrated mild bilateral conductive hearing loss. Derbent et al. (2011) tabulated the clinical findings of 11 previously reported patients with Keipert syndrome and compared them to this patient, noting that the associated hearing loss was usually sensorineural rather than conductive. They stated that fibrous dysplasia had not previously been reported in the disorder, and could be coincidental or might represent an infrequent manifestation of Keipert syndrome.
Amor et al. (2019) studied 10 male patients from 6 families with Keipert syndrome, including 3 from the family originally reported by Keipert et al. (1973), who all had mutations in the GPC4 gene. Clinical features present in 7 or more affected individuals included macrocephaly, prominent forehead, flat midface, hypertelorism, broad nose, downturned corners of mouth, and digital abnormalities. The most prominent peripheral skeletal features were brachydactyly, clinodactyly and/or camptodactyly, broad terminal phalanges, and broad thumbs and great toes; 2 patients also exhibited absent toenails. Cognitive impairment was variable, with some showing average intelligence and others showing borderline to moderate intellectual disability. In addition, autism or autistic features were observed in 3 affected individuals. Although sensorineural deafness was described initially as a cardinal feature of Keipert syndrome, deafness was not observed in any of the other families with confirmed GPC4 pathogenic variants, suggesting that deafness might be relatively infrequent in Keipert syndrome.
Amor et al. (2007) described additional male family members of the original family described by Keipert et al. (1973) and suggested that the pedigree was consistent with X-linked inheritance.
The pattern of transmission of Keipert syndrome in the families reported by Amor et al. (2019) was consistent with X-linked inheritance.
Amor et al. (2007) concluded that Keipert syndrome is an X-linked form of syndromic deafness. Linkage analysis using microsatellite markers in the originally described family along the X chromosome gave suggestive linkage of the disorder to Xq22.2-q28 with a lod score of 1.20.
In 10 male patients from 6 families with Keipert syndrome, Amor et al. (2019) identified hemizygosity for truncating or frameshift mutations in the GPC4 gene on chromosome Xq26 (e.g., 300168.0001-300168.0004) that segregated with disease and were inherited from a carrier mother. Carrier females were clinically unaffected, although 1 mother demonstrated subtle dysmorphic features including hypertelorism and flat nasal bridge. X-inactivation studies in carrier females from 3 families demonstrated extreme skewing in all of them (greater than 90% methylation of 1 allele).
Exclusion Studies
Amor et al. (2019) analyzed genomic DNA from 1 female and 3 male patients previously reported as having Keipert syndrome (Reardon and Hall, 2003; Dumic et al., 2006; Derbent et al., 2011), but did not detect any GPC4 variants. Amor et al. (2019) suggested that these individuals, who all exhibited hearing loss, had an overlapping but distinct disorder.
Dumic et al. (2006) reported a 10-year-old girl with characteristic features of Keipert syndrome, including broad terminal phalanges, especially of the thumb and hallux, sensorineural deafness, large head circumference, broad forehead and nasal bridge, hypertelorism, bilateral epicanthic folds, maxillary hypoplasia, and hoarse voice. Her father was mildly affected, with broad terminal phalanges of thumb and hallux, large head circumference, broad nasal bridge, maxillary hypoplasia, and hoarse voice. Other members of the family were said to have broad terminal phalanges and the characteristic facial appearance. Dumic et al. (2006) stated that the phenotype of their proposita, the first female reported with Keipert syndrome, was very similar to that described by Reardon and Hall (2003) in a 7.5-year-old boy, and noted that the inheritance pattern in this family appeared to be autosomal dominant.
Noting that Amor et al. (2007) had mapped Keipert syndrome to the X chromosome, Nik-Zainal et al. (2008) stated that, given the report of an affected girl (Dumic et al., 2006), further data were needed before the mapping and mode of inheritance could be certain.
Amor, D. J., Dahl, H.-H. M., Bahlo, M., Bankier, A. Keipert syndrome (nasodigitoacoustic syndrome) is X-linked and maps to Xq22.2-Xq28. Am. J. Med. Genet. 143A: 2236-2241, 2007. [PubMed: 17726694] [Full Text: https://doi.org/10.1002/ajmg.a.31917]
Amor, D. J., Stephenson, S. E. M., Mustapha, M., Mensah, M. A., Ockeloen, C. W., Lee, W. S., Tankard, R. M., Phelan, D. G., Shinawi, M., de Brouwer, A. P. M., Pfundt, R., Dowling, C., and 18 others. Pathogenic variants in GPC4 cause Keipert syndrome. Am. J. Hum. Genet. 104: 914-924, 2019. [PubMed: 30982611] [Full Text: https://doi.org/10.1016/j.ajhg.2019.02.026]
Balci, S., Dagli, S. Keipert syndrome in two brothers from Turkey. Clin. Genet. 50: 223-228, 1996. [PubMed: 9001804] [Full Text: https://doi.org/10.1111/j.1399-0004.1996.tb02631.x]
Derbent, M., Bikmaz, Y. E., Agildere, M. A patient with Keipert syndrome and isolated fibrous dysplasia of the sphenoid sinus. (Letter) Am. J. Med. Genet. 155A: 1496-1499, 2011. [PubMed: 21567928] [Full Text: https://doi.org/10.1002/ajmg.a.34006]
Dumic, M., Kokic, D. D., Matic, T., Potocki, K. Daughter and her mildly affected father with Keipert syndrome. Am. J. Med. Genet. 140A: 2488-2492, 2006. [PubMed: 17036315] [Full Text: https://doi.org/10.1002/ajmg.a.31489]
Keipert, J. A., Fitzgerald, M. G., Danks, D. M. A new syndrome of broad terminal phalanges and facial abnormalities. Aust. Paediat. J. 9: 10-13, 1973. [PubMed: 4708024] [Full Text: https://doi.org/10.1111/j.1440-1754.1973.tb02215.x]
Nik-Zainal, S., Holder, S. E., Cruwys, M., Hall, C. M., Shaw-Smith, C. Keipert syndrome: two further cases and review of the literature. Clin. Dysmorph. 17: 169-175, 2008. [PubMed: 18541962] [Full Text: https://doi.org/10.1097/MCD.0b013e3282f4afc3]
Reardon, W., Hall, C. M. Broad thumbs and halluces with deafness: a patient with Keipert syndrome. Am. J. Med. Genet. 118A: 86-89, 2003. [PubMed: 12605449] [Full Text: https://doi.org/10.1002/ajmg.a.10063]