ORPHA: 589856;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.12 | Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome | 620186 | Autosomal dominant | 3 | KMT2D | 602113 |
A number sign (#) is used with this entry because of evidence that branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH) is caused by heterozygous mutation in the KMT2D gene (602113) on chromosome 12q13.
Branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome (BCAHH) is an autosomal dominant disorder characterized by choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. Additional features may include developmental delay, impaired intellectual development, and growth failure/retardation (summary by Cuvertino et al., 2020 and Baldridge et al., 2020).
Al-Gazali et al. (2002) reported a brother and sister from an inbred Arab family with an autosomal recessive syndrome of choanal atresia, hypothelia/athelia, and thyroid gland anomalies. The sister died at 4 months of age. The authors noted that the features overlapped those of Bamforth syndrome (241850), HEDH syndrome (225050), and methimazole embryopathy.
Cuvertino et al. (2020) reported 9 patients from 7 families, including the family reported by Al-Gazali et al. (2002), with overlapping features and a mutation in the KMT2D gene. The patients ranged in age from 34 days to 35 years and 2 were deceased at age 28 days and 4 months. Patients from family 4 had previously been reported by Al-Gazali et al. (2002). Seven patients had branchial sinus and/or neck pits, 8 had hearing loss, 6 had external ear abnormalities, 7 had abnormalities of the lacrimal duct, and 7 had choanal atresia. Athelia or hypoplastic nipples was seen in 6 patients, and 3 patients had congenital heart disease (atrial septal defect, right ventricular hypertrophy, patent foramen ovale, and/or persistent pulmonary hypertension of the newborn). Thyroid abnormalities and/or hypothyroidism were diagnosed in 6 patients, and 4 patients had recurrent infections or immune abnormalities. Five patients had feeding difficulties and 5 patients had short stature.
Baldridge et al. (2020) reported 4 unrelated patients, aged 14 to 24 years, with similar features and mutation in the KMT2D gene. One patient died at 14 years of age from a hypoglycemic coma. All 4 patients had developmental delay and 3 had impaired intellectual development. All patients had growth retardation/failure, 2 had low IGF1 levels, and 1 was growth hormone deficient. All patients had hearing loss and external ear abnormalities or ear pits, and all had hypothyroidism, which was central hypothyroidism on 1 patient who had pituitary hypoplasia. All had choanal atresia and athelia or hypoplastic nipples. All had hypoparathyroidism, which was transient in 1 patient. Two patients had absent pubertal development, and 1 patient had uterine hypoplasia and hypogonadotrophic hypogonadism. Two patients had insulin-dependent diabetes mellitus. Two patients had branchial cleft fistula and 2 had lacrimal duct abnormalities. Two patients had interstitial lung disease.
The transmission pattern of BCAHH in the families reported by Cuvertino et al. (2020) was consistent with autosomal dominant inheritance.
In 9 patients from 7 families with branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome, including 2 sibs previously reported by Al-Gazali et al. (2002), Cuvertino et al. (2020) identified heterozygous mutations in exons 38 or 39 of the KMT2D gene (602113.0006-602113.0009). Recombinant KMT2D with each of the mutations did not have abnormal H3K4 trimethylation activity but had a perturbed secondary structure. Methylation profiles of peripheral blood from 4 of the patients with BCAHH were distinct from methylation profiles observed in 4 patients with Kabuki syndrome (see 147920) and 4 patients with CHARGE syndrome (214800), suggesting that these are each epigenetically distinct disorders. Methylated CpG sites in peripheral blood from patients with BCAHH were enriched for CpG sites corresponding to genes associated with head morphology, embryonic development, cell proliferation and body axis development. Patients with BCAHH did not meet clinical criteria for Kabuki syndrome and had distinct clinical features.
In 4 unrelated patients with BCAHH, including a patient previously reported by Sakata et al. (2017), Baldridge et al. (2020) identified de novo heterozygous missense mutations in the KMT2D gene (see, e.g., 602113.0006; 602113.0010-602113.0011). The mutations were identified by whole-exome sequencing. Functional studies were not performed. The authors noted similarity to CHARGE syndrome.
Al-Gazali, L. I., Hamid, Z., Hertecant, J., Bakir, M., Nath, D., Kakadekar, A. An autosomal recessive syndrome of choanal atresia, hypothelia/athelia and thyroid gland anomalies overlapping Bamforth syndrome, ANOTHER syndrome and methimazole embryopathy. Clin. Dysmorph. 11: 79-85, 2002. [PubMed: 12002153] [Full Text: https://doi.org/10.1097/00019605-200204000-00001]
Baldridge, D., Spillmann, R. C., Wegner, D. J., Wambach, J. A., White, F. V., Sisco, K., Toler, T. L., Dickson, P. I., Cole, F. S., Shashi, V., Grange, D. K. Phenotypic expansion of KMT2D-related disorder: beyond Kabuki syndrome. Am. J. Med. Genet. 182A: 1053-1065, 2020. [PubMed: 32083401] [Full Text: https://doi.org/10.1002/ajmg.a.61518]
Cuvertino, S., Hartill, V., Colyer, A., Garner, T., Nair, N., Al-Gazali, L., Canham, N., Faundes, V., Flinter, F., Hertecant, J., Holder-Espinasse, M., Jackson, B., and 23 others. A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome. Genet. Med. 22: 867-877, 2020. Note: Erratum: Genet. Med. 22: 980 only, 2020. [PubMed: 31949313] [Full Text: https://doi.org/10.1038/s41436-019-0743-3]
Sakata, S., Okada, S., Aoyama, K., Hara, K., Tani, C., Kagawa, R., Utsunomiya-Nakamura, A., Miyagawa, S., Ogata, T., Mizuno, H., Kobayashi, M. Individual clinically diagnosed with CHARGE syndrome but with a mutation in KMT2D, a gene associated with Kabuki syndrome: a case report. Front. Genet. 8: 210, 2017. [PubMed: 29321794] [Full Text: https://doi.org/10.3389/fgene.2017.00210]