Abnormal Hair, Joint Laxity, And Developmental Delay

A number sign (#) is used with this entry because of evidence that abnormal hair, joint laxity, and developmental delay (HJDD) is caused by compound heterozygous mutation in the HEPHL1 gene (618455) on chromosome 11q21. One such patient has been reported.

Description

Abnormal hair, joint laxity, and developmental delay (HJDD) is characterized by normal hair at birth that gradually becomes sparse, twisted, brittle, and easily broken, with pili torti and trichorrhexis nodosa observed on light microscopy. Other features include increased joint mobility and cognitive delay (Sharma et al., 2019).

Clinical Features

Among the children of a healthy Puerto Rican couple related as first cousins, Shapira et al. (1992) observed a brother and sister with growth and developmental delay, mild to moderate neurologic abnormalities, and pili torti with unusual findings in the hair shafts on electron microscopy. The sibs' newborn hair was gradually replaced with kinky brittle hair of lighter color, and at ages 7 years and 5.5 years, their scalp hair was sparse, thin, and kinky, with a yellow-orange color that faded upon sun exposure. They exhibited mild ligamentous laxity and were myopic, but hearing tests were normal. Their developmental milestones had been delayed compared to older sibs, and they showed mild generalized hypotonia and mild to moderate truncal ataxia with broad-based unsteady gait. Laboratory evaluation revealed mildly elevated serum lactate and copper levels, with normal serum ceruloplasmin and 24-hour urinary copper excretion. Light microscopy showed thin hair shafts with abnormal twisting and irregular shapes but no banding under polarized light; electron microscopy showed cuticle erosions and transverse fissures. Quadriceps muscle biopsy showed fiber atrophy and a tendency to fiber-type grouping, suggestive of chronic mild neurogenic atrophy. Shapira et al. (1992) concluded that 'these sibs represent a distinct, previously unreported, probably autosomal recessive syndrome.'

Sharma et al. (2019) reported a 5-year-old boy of Native American and Mexican descent who had abnormal hair and cognitive dysfunction. At birth his hair was thick, black, and distributed evenly on his scalp, but in infancy he experienced anterior hair loss that progressed to total alopecia by 6 months of age. At age 3, his mother noticed a regression in acquired skills, and evaluation showed his language ability to be equivalent to 21 months with poor articulation. On examination at age 5 years, he had elfin facies, absent lateral third of eyelashes, sparse eyebrows, and coarse hair texture with a patchy distribution. Published photographs showed hair to be orangish-brown in color. Light microscopy of short and long hairs revealed pili torti and trichorrhexis nodosa. Other features in the proband included brittle hypoplastic nails and increased mobility of all joints, especially the thumbs. He had attention-deficit/hyperactivity disorder, which responded well to medication. His gait, muscle tone, strength, and reflexes were normal. Serum copper and ceruloplasmin levels were normal.

Molecular Genetics

In a 5-year-old boy with abnormal hair, joint laxity, and developmental delay, Sharma et al. (2019) performed whole-exome sequencing and identified compound heterozygosity for mutations in the HEPHL1 gene (618455.0001 and 618455.0002), inherited from his unaffected parents. The mutations were present in the ExAC and gnomAD databases, but at extremely low frequencies and not in homozygosity.