Mental retardation, premature balding, small genitalia, small acra and small patellae in brothers: Confirmation of an entity

We describe two brothers with moderate to severe mental retardation, short stature, an unusual skull shape, early anterior balding, unusual facial morphology, hypogonadotrophic hypogonadism, small genitalia, and small patellae. The older sib had generalized hypotonia without focal neurological abnormalities or myotonia. His brother had epileptic fits in infancy and tonic-clonic seizures from 5 years on, and died at 8 years of age during a seizure with possibly an intra-cerebral haemorrhage. Both brothers had a very similar face characterized by a high anterior hair line, small and upslanting palpebral fissures, deeply set eyes, a broad nasal tip, and everted lower lip. Additional studies in the older sib included a CGH array, and molecular testing of PQBP1 and FRAXA, all with normal results. Investigations of maternal lymphocytes showed completely skewed X-inactivation.The phenotype in the sibs resembles the phenotype reported in three unrelated patients reported by Scholte et al. in 1991 (MIM %181515) and Fryns et al. in 1993, and confirms this to be a clinically distinct entity. As all reported cases have been males, including two brothers, none of the parents were consanguineous, cytogenetic studies failed to show abnormalities, and X-inactivation was completely skewed in one of the mothers, we suggest this entity to follow an X-linked recessive pattern of inheritance.