CDKN2A germline splicing mutation affecting both p16(ink4) and p14(arf) RNA processing in a melanoma/neurofibroma kindred.

The CDKN2A locus encodes two tumor suppressor proteins, p16(ink4) and p14(arf), through use of alternative first exons. CDKN2A mutations detected in melanoma families are usually missense or nonsense changes which mainly impair p16(ink4) function. Large genomic deletions spanning the entire locus have been observed in two pedigrees with melanomas and nervous tumors. We have detected a novel splice site mutation in a family with melanomas, neurofibromas, and multiple dysplastic nevi. Both alternative mRNAs produced by the mutant allele lacked shared sequences from exon 2, which encodes a substantial portion (>50%) of both p16(ink4) and p14(arf) proteins. The development of neurofibromas can be explained by cooperative effects of combined inactivation of p16(ink4) and p14(arf) or, alternatively, of p14(arf) alone.

Dicentric chromosome Y associated with Leydig cell agenesis and sex reversal.

The nature of a non-mosaic marker Y chromosome observed in a pseudohermaphrodite patient with Leydig cell agenesis was investigated by high-resolution chromosome analysis and molecular probes from the Y chromosome. Cytogenetically, the marker chromosome appeared to be an isodicentric, with breakage in Yq11.21. Double copies of all Yp-specific loci tested, including SRY, were present. The most distal Yq portion detected in patient DNA was DXS278-C, which maps to interval D in the chromosome Yq deletion map. Fragment DXS278-B, which maps to deletion interval E, was absent. The possible relationship between this cytogenetic abnormality and Leydig cell agenesis, a finding never reported in association with Y chromosome rearrangements, is discussed.

Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology.

In 1977 Costello described two unrelated children with poor postnatal growth, mental retardation, curly hair, coarse face of similar appearance, and nasal papillomata, suggesting the existence of a previously undescribed syndrome of uncertain familial nature [Costello, Aust Paediatr J 13: 114-118, 1977]. The existence of this syndrome as a separate entity was substantiated several years later by two additional reports by Der Kaloustian et al. [Am J Med Genet 43:678-685, 1991] and Martin and Jones [Am J Med Genet 41:346-349, 1991]. More recently Borochowitz et al. [Am J Med Genet 43:678-685, 1992] described a new "multiple congenital anomalies/mental retardation syndrome with facio-cutaneous-skeletal involvement." Whether this condition should be considered separately from the Costello syndrome is currently a matter of debate. We present three cases, two of whom are sibs, who support the identity of the two syndromes. Our aim is to better redefine the diagnostic criteria, describe the natural history, and confirm the genetic cause of the Costello syndrome, whose pattern of inheritance is most likely autosomal recessive.

Cerebro-reno-digital (Meckel-like) syndrome with Dandy-Walker malformation, cystic kidneys, hepatic fibrosis, and polydactyly.

We report on a boy with several findings of the Meckel syndrome, such as hepatic fibrosis, polycystic kidneys, post-axial hexadactyly, and genital abnormalities, but a Dandy-Walker malformation rather an occipital meningocele. Progressive deterioration of renal function beginning at 37 months led to death at 43 months. Both Dandy-Walker malformation and survival to the fourth year are unusual findings in Meckel syndrome. This uncommon combination represents a further demonstration of the pleiotropy/heterogeneity of the cerebro-reno-digital syndromes.

The Perlman syndrome: familial renal dysplasia with Wilms tumor, fetal gigantism and multiple congenital anomalies.

We describe a familial syndrome of renal dysplasia, Wilms tumor, hyperplasia of the endocrine pancreas, fetal gigantism, multiple congenital anomalies and mental retardation. This condition was previously described by Perlman et al [1973, 1975] and we propose to call it the "Perlman syndrome." It appears to be transmitted as an autosomal recessive trait. The possible relationships between dysplasia, neoplasia and malformation are discussed.