Alternative titles; symbols
SNOMEDCT: 721874001; ORPHA: 2319;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p21.1 | Juberg-Hayward syndrome | 216100 | Autosomal recessive | 3 | ESCO2 | 609353 |
A number sign (#) is used with this entry because of evidence that Juberg-Hayward syndrome (JHS) is caused by homozygous mutation in the ESCO2 gene (609353) on chromosome 8p21.
Juberg-Hayward syndrome (JHS) is characterized by cleft lip and palate, rhizomelia of the upper limbs with limited elbow extension due to humeroradial synostosis or dislocation of the radial head, and digital anomalies, including shortened thumbs and index and fifth fingers. Microcephaly has been observed in some patients (Kantaputra et al., 2020).
Juberg and Hayward (1969) described a syndrome with oral, cranial, and digital manifestations in 5 of 6 children of normal, unrelated parents. Two brothers had cleft lip and palate, microcephaly, hypoplasia and distal placement of the thumbs, and elbow deformities limiting extension. One of the brothers had toe anomalies, as did 3 of the 4 sisters. Among the sisters microcephaly, stiff thumbs, and forme fruste cleft lip were observed.
Kingston et al. (1982) described a single case. In addition to unilateral cleft lip and palate, the 17-year-old boy had bilateral absent thumbs, anomalous carpal bones, deformity of the radial heads, and short stature (143.3 cm). He was found to have growth hormone deficiency. The sella turcica was normal by x-ray.
Nevin et al. (1981) reported a case in a female who had absence of the pituitary fossa but no evident endocrine dysfunction to account for short stature.
Verloes et al. (1992) described 3 nonfamilial cases of orocraniodigital syndrome. The main features were cleft lip/palate, hypertelorism, bowed and upward slanting eyebrows, thumb hypo/aplasia or proximal/distal thumb displacement, luxation of the radial head, elbow restriction, minor vertebral and rib anomalies and horseshoe kidneys. New features observed by Verloes et al. (1992) were mental retardation (not correlated with the severity of malformations), anterior anal displacement, and ptosis. Verloes et al. (1992) thought that recessive inheritance was likely but that autosomal dominant inheritance could not be totally excluded, making it wise to exercise caution in the genetic counseling of the parents of an affected child and of affected patients themselves.
Silengo and Tornetta (2000) reported a 10-year-old male with Juberg-Hayward syndrome. He had a cleft palate, distally placed thumbs, and multiple cervical hemivertebrae, but did not have a cleft lip. The parents were unrelated, and there was advanced parental age of 42. The mode of inheritance was unclear.
Kantaputra and Mongkolchaisup (1999) described a 7-year-old Thai boy, born of first-cousin parents, who had short stature and microcephaly, bilateral cleft lip and palate with protruding premaxilla, and markedly restricted pronation and supination of the forearm with fixation of the elbow at 90 degrees due to humeroradial synostosis. Additional dysmorphic features included frontal bossing, midface hypoplasia, depressed nasal bridge, hypertelorism, bilateral ptosis, and hypodontia. The patient also exhibited digital anomalies, including short immobile proximally placed thumbs, short index and fifth fingers, and cutaneous syndactyly of the second and third toes. X-rays showed delayed bone age and a hypoplastic and subluxated ulna, as well as hypoplastic middle phalanges of the index and fifth fingers, and hypoplastic and hypocalcified first metacarpal and proximal and distal phalanges of the thumb. The proband also had motor delay and occasional simple partial seizures with secondary generalization; electroencephalogram showed definite epileptiform discharge over the right frontal region. The authors stated that the patient exhibited characteristic features of Juberg-Hayward syndrome together with new findings of humeroradial synostosis, carpal anomalies, simian crease, brachydactyly A4, widely spaced nipples, seizures, and myopia.
Reardon et al. (2001) reported a 9-year-old boy whose clinical presentation resembled Malpuech syndrome (3MC3; 248340), but who had radiologic features similar to those seen in patients with Juberg-Hayward syndrome. Clinical features in this patient consistent with both syndromes included short stature, hypertelorism, and cleft lip/palate; but he also had renal agenesis, umbilical hernia, and shawl scrotum, which had not been reported in Juberg-Hayward syndrome but had been seen in Malpuech syndrome. Radiologic features consistent with Juberg-Hayward syndrome included mesomelic shortening, elbow dislocation, carpal bone abnormalities, mild scoliosis, and vertebral endplate irregularity. Reardon et al. (2001) suggested that the Malpuech and Juberg-Hayward syndromes may be allelic.
Hedera and Innis (2003) reported a 14-year-old male with absent thumbs, bilateral cleft lip/palate, and microcephaly, severe mental retardation, severe skeletal abnormalities, as well as a facial appearance supporting the diagnosis of Juberg-Hayward syndrome. New findings in this patient included Dandy-Walker abnormality, hypospadias, and oral abnormalities, expanding the clinical spectrum of this syndrome. Hedera and Innis (2003) suggested possible overlap with orofaciodigital (see 258850) and Malpuech (248340) syndromes.
Kantaputra et al. (2020) restudied the Thai patient originally reported by Kantaputra and Mongkolchaisup (1999), then aged 27 years, and his similarly affected 15-year-old brother. Born of first-cousin parents from the Lisu tribe, both had short stature with normal head circumference. Clinical features found in the older brother but not in the younger included bilateral cleft lip and palate, bilateral humeroradial synostosis, simple partial seizure with secondary generalization, and bilateral ptosis. The younger brother had unilateral cleft lip and palate, dislocation of the radial heads, and cutaneous syndactyly of the fingers. The authors concluded that microcephaly is a common but inconsistent feature of the syndrome, and noted that the presence of humeroradial synostosis and radial head dislocation in the same family is consistent with both being in the same spectrum of forearm malformations.
Kantaputra et al. (2021) described a 2-year-old Thai girl from the Lisu tribe who had proportionate short stature, microcephaly, ptosis, hanging nasal columella, and repaired cleft lip and palate. Her fingers were short, with the second and fifth fingers more severely shortened, and she had fifth-finger clinodactyly. In addition, she had bilateral cutaneous syndactyly between fingers 2-3 and 4-5. Elbow joint movement had been limited from birth, with marked restriction of pronation and supination. Radiographic examination revealed bilateral humeroradial synostosis, with shortening of the metacarpals and phalanges of the thumbs as well as proximal and middle phalanges of the second and fifth fingers. In addition, the carpal bones showed delayed bone age.
The transmission pattern of Juberg-Hayward syndrome in the family reported by Kantaputra et al. (2020) was consistent with autosomal recessive inheritance.
In 2 Thai brothers from the Lisu tribe with Juberg-Hayward syndrome, Kantaputra et al. (2020) identified homozygosity for a nonsense mutation in the ESCO2 gene (R552X; 609353.0008) that segregated with disease in the family. Cytogenetic testing revealed premature centromere separation or lack of cohesion at the centromeric heterochromatic regions in both patients.
In a 2-year-old Thai girl from the Lisu tribe with Juberg-Hayward syndrome, Kantaputra et al. (2021) identified homozygosity for the R552X mutation in the ESCO2 gene.
Hedera, P., Innis, J. W. Juberg-Hayward syndrome: report of a new patient with severe phenotype and novel clinical features. Am. J. Med. Genet. 122A: 257-260, 2003. [PubMed: 12966528] [Full Text: https://doi.org/10.1002/ajmg.a.20263]
Juberg, R. C., Hayward, J. R. A new familial syndrome of oral, cranial, and digital anomalies. J. Pediat. 74: 755-762, 1969. [PubMed: 5778829] [Full Text: https://doi.org/10.1016/s0022-3476(69)80138-1]
Kantaputra, P. N., Dejkhamron, P., Intachai, W., Ngamphiw, C., Kawasaki, K., Ohazama, A., Krisanaprakornkit, S., Olsen, B., Tongsima, S., Ketudat Cairns, J. R. Juberg-Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2. Europ. J. Orthod. 43: 45-50, 2021. [PubMed: 32255174] [Full Text: https://doi.org/10.1093/ejo/cjaa023]
Kantaputra, P. N., Dejkhamron, P., Tongsima, S., Ngamphiw, C., Intachai, W., Ngiwsara, L., Sawangareetrakul, P., Svasti, J., Olsen, B., Cairns, J. R. K., Bumroongkit, K. Juberg-Hayward syndrome and Roberts syndrome are allelic, caused by mutations in ESCO2. Arch. Oral Biol. 119: 104918, 2020. Note: Electronic Article. [PubMed: 32977150] [Full Text: https://doi.org/10.1016/j.archoralbio.2020.104918]
Kantaputra, P. N., Mongkolchaisup, S. Juberg-Hayward syndrome: a new case report and clinical delineation of the syndrome. Clin. Dysmorph. 8: 123-127, 1999. [PubMed: 10319201]
Kingston, H. M., Hughes, I. A., Harper, P. S. Orocraniodigital (Juberg-Hayward) syndrome with growth hormone deficiency. Arch. Dis. Child. 57: 790-792, 1982. [PubMed: 7138070] [Full Text: https://doi.org/10.1136/adc.57.10.790]
Nevin, N. C., Henry, P., Thomas, P. T. S. A case of the orocraniodigital (Juberg-Hayward) syndrome. J. Med. Genet. 18: 478-480, 1981. [PubMed: 6278147] [Full Text: https://doi.org/10.1136/jmg.18.6.478]
Reardon, W., Hall, C. M., Gorman, W. An atypical case suggesting the possibility of overlap between Malpuech and Juberg-Hayward syndromes. Clin. Dysmorph. 10: 123-128, 2001. [PubMed: 11310992] [Full Text: https://doi.org/10.1097/00019605-200104000-00009]
Silengo, M., Tornetta, L. Juberg-Hayward syndrome: report of a case with cleft palate, distally placed thumbs and vertebral anomalies. Clin. Dysmorph. 9: 127-129, 2000. [PubMed: 10826626] [Full Text: https://doi.org/10.1097/00019605-200009020-00011]
Verloes, A., Le Merrer, M., Davin, J.-C., Wittamer, P., Abrassart, C., Bricteux, G., Briard, M.-L. The orocraniodigital syndrome of Juberg and Hayward. J. Med. Genet. 29: 262-265, 1992. [PubMed: 1583649] [Full Text: https://doi.org/10.1136/jmg.29.4.262]