Melnick-Needles Syndrome

A number sign (#) is used with this entry because Melnick-Needles syndrome (MNS) is caused by mutation in the FLNA gene (300017) on chromosome Xq28.

Description

Melnick-Needles syndrome is 1 of 4 otopalatodigital syndromes caused by mutations in the FLNA gene. These disorders, including frontometaphyseal dysplasia (FMD; 305620), otopalatodigital syndrome-1 (OPD1; 311300), and otopalatodigital syndrome-2 (OPD2; 304120), constitute a phenotypic spectrum. At the mild end of the spectrum, males with OPD1 have cleft palate and mild skeletal anomalies with conductive deafness caused by ossicular anomalies. FMD is characterized by a generalized skeletal dysplasia, deafness and urogenital defects. Males with OPD2 have disabling skeletal anomalies in addition to variable malformations in the hindbrain, heart, intestines, and kidneys that frequently lead to perinatal death. The most severe phenotype, MNS, is characterized by a skeletal dysplasia in the heterozygote. Affected males exhibit severe malformations similar to those observed in individuals with OPD2, resulting in prenatal lethality or death in the first few months of life (review by Robertson, 2005). Verloes et al. (2000) suggested that these disorders constitute a single entity, which they called 'fronto-otopalatodigital osteodysplasia.'

Clinical Features

Melnick and Needles (1966) described families that contained multiple cases in multiple generations of a severe congenital bone disorder characterized by typical facies (exophthalmos, full cheeks, micrognathia and malalignment of teeth), flaring of the metaphyses of long bones, s-like curvature of bones of legs, irregular constrictions in the ribs, and sclerosis of base of skull. Male-to-male transmission was thought to have occurred in 1 instance. Ureteral obstruction was observed in the original case (Melnick and Needles, 1966) and in several others reported.

'Osteodysplasty' was the term suggested by Coste et al. (1968), who described an affected 58-year-old woman. Bone disease was recognized in infancy when she began to walk. Normal childbirth was impossible because of contracted pelvis. Osteoarthritis of the lumbar spine and hips gave much pain. Her height was normal. Striking facies comprised frog-like eyes, high forehead, full red cheeks, and receding chin. X-rays showed curved long bones, tortuous ribboned ribs, and deformed clavicles, scapula, and pelvis.

Beighton and Hamersma (1980) speculated that frontometaphyseal dysplasia and osteodysplasty (MNS) may be due to the same gene. They suggested that the gene may be X-linked and that the former condition is the usual phenotype in hemizygous males and the latter condition the usual phenotype in heterozygous females. They pointed out that the manifestations in Melnick and Needles' 2 kindreds (13 affected persons; 9 females, 4 males) were highly variable. Apart from one doubtful instance, no male-to-male transmission was reported.

Features emphasized by Kozlowski (1993) on the basis of 9 cases included small, deformed chest, large anterior fontanel associated with prominent forehead, and high vertebrae. One of his patients was diagnosed at the age of 37 years. All were female.

Kristiansen et al. (2002) reported 2 severely affected girls with Melnick-Needles syndrome and their mildly affected mother. They analyzed the X-chromosome inactivation pattern in this family to determine if it was related to the variable phenotype. A very skewed inactivation pattern was observed in the blood from both the mildly affected mother and one of her daughters, whereas a highly skewed inactivation pattern in buccal smear DNA was observed in the mother only. X inactivation, therefore, did not explain the variable phenotype in this family.

Males Born to Affected Mothers

Von Oeyen et al. (1981) observed an affected woman whose son, who died soon after birth, was also affected. The son had omphalocele and hypoplastic kidneys. Von Oeyen et al. (1982) reported a severely affected male with multiple congenital anomalies who was born of an affected mother and died soon after birth. A similar case was reported by Theander and Ekberg (1981). Zackai et al. (1986) and Donnenfeld et al. (1987) described a lethally affected male fetus identified prenatally in a woman with oligohydramnios and MNS. The condition was detected sonographically at 16 weeks' gestation. Autopsy on the electively aborted fetus showed exophthalmos, prune belly sequence with urethral atresia and megacystis, tetralogy of Fallot, atrioventricular canal defect, and complete malrotation of the gut. Krajewska-Walasek et al. (1987) found 6 examples of this syndrome in males: there were 3 well-documented lethal examples of the disorder among the offspring of affected females and 3 examples in males born to normal parents and presumably representing new mutations. One of the patients described in detail died of pneumonia at age 3 after having repeated bouts of pneumonia.

Van der Lely et al. (1991) described typical features in an 11-year-old black male who was the sixth of 8 children of healthy, unrelated parents. He may be the oldest surviving male with this disorder.

Neou et al. (1996) described a mother with Melnick-Needles syndrome whose son had partial manifestations of the syndrome. His facial features were similar to those of his mother. He was not short, but was mentally retarded. His radiologic examination showed sclerotic skull base, ribbon-like flaring of ribs, short bowed clavicles, small pelvis with thin iliac crest, and moderate flaring of the distal part of the long bones. In addition, he had atrial septal defect, pulmonic stenosis, intestinal malrotation, and ectopic kidney. Neou et al. (1996) proposed that Melnick-Needles syndrome is not always lethal in males born to affected mothers.

Verloes et al. (2000) reported a mild case of OPD2, a severe case of OPD2 with anomalies of the central nervous system and some manifestations of frontometaphyseal dysplasia, a lethal case of OPD2 with similarities to Melnick-Needles syndrome, and 3 unrelated boys born to mothers with MNS (1 with a severe form, 1 with a lethal form, and an aborted fetus). They reviewed the features in these disorders and in OPD1 and suggested that these disorders constitute a single entity.

Inheritance

Melnick-Needles syndrome is an X-linked dominant disorder. Most cases described are in females. Nyhan and Sakati (1976) described a family with 4 affected females in 3 successive generations. Von Oeyen et al. (1982) found a sex ratio of 21 females and 3 males in reported cases. Melnick (1982) studied 4 additional families in the United States; in two, 3 generations were affected and in the other two, 2 generations. The Melnick-Needles syndrome had been assumed to be an autosomal dominant disorder. However, Gorlin and Knier (1982) analyzed reported families with restudy of some. Melnick had reexamined the male 'cases' in the kindred he reported in 1966 and found them in fact to be normal. In all, Gorlin and Knier (1982) found 23 patients in 15 pedigrees. Most cases were sporadic and may represent new mutations. In only 3 pedigrees was there transmission from one generation to the next, always female to female.

Ter Haar et al. (1982) suggested autosomal recessive inheritance on the basis of a kindred with an affected brother and sister and their affected fourth cousin. This disorder was later characterized as a distinct entity and named Frank-ter Haar syndrome (249420).

See also review by Wettke-Schafer and Kantner (1983).

Pathogenesis

Svejcar (1983) found an increased content of collagen; the sclerosing bone process may be an expression thereof. Fryns et al. (1988) emphasized hyperlaxity of skin and joints as suggesting that this condition is a generalized connective tissue disorder.

Molecular Genetics

X-linked inheritance is established by the demonstration of Robertson et al. (2003) that Melnick-Needles syndrome is caused by gain-of-function mutations in the gene encoding filamin A (FLNA; 300017). Mutations in the FLNA gene were found in 12 presumably unrelated patients with Melnick-Needles syndrome, all female. All had mutations in exon 22 of the gene. One mutation was found in 6 individuals, a second mutation in 5, and a third mutation in a single case.

Robertson et al. (2006) identified a mutation in the FLNA gene (300017.0013) in a girl with Melnick-Needles syndrome. The girl had an unaffected twin sister who did not carry the mutation; the unaffected mother also did not carry the mutation. The twins were born with separate amniotic sacs within a single chorion, and zygosity analysis indicated a high probability that the girls were monozygotic twins. Robertson et al. (2006) concluded that the FLNA mutation occurred postzygotically in the affected twin and emphasized the importance of the finding for genetic counseling.