Phenotypic overlap in Melnick–Needles, serpentine fibula–polycystic kidney and Hajdu–Cheney syndromes: a clinical and molecular study in three patients

Abstract

Several disorders characterized primarily by anomalies of the skeleton have recently been shown to be caused by mutations in the X-linked gene, FLNA. One of these conditions, the Melnick-Needles syndrome exhibits a phenotype that shares overlap with that of serpentine fibula-polycystic kidney syndrome and the autosomal dominant condition, Hajdu-Cheney syndrome. Here, we describe three individuals with these diagnoses. The individual with serpentine fibula-polycystic kidney syndrome, the fifth case reported in the literature, exhibited wormian bones which further expands the phenotypic spectrum for this condition and extends the overlap with Hajdu-Cheney syndrome. All three members of the filamin gene family, FLNA, and its functionally related paralogues, FLNB and FLNC, were screened for pathogenic mutations in all three individuals. We found a mutation in FLNA in the individual with Melnick-Needles syndrome, but no pathogenic variants in any filamin gene in the two individuals with Hajdu-Cheney syndrome and serpentine fibula-polycystic kidney syndrome. Clinical and molecular evidence indicates that Melnick-Needles syndrome is aetiologically distinct from Hajdu-Cheney syndrome and serpentine fibula-polycystic kidney syndrome, but these two latter conditions share many clinical similarities and may prove to be allelic to one another.

Hajdu–Cheney syndrome with severe dural ectasia

“…Most likely HCS is caused by a gene defect. FLNA, FLNB, and FLNC genes, encoding filamin A, B, and C, respectively, were excluded earlier as causative genes in a single HCS patient [Albano et al, 2007].…”

Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu–Cheney syndrome

“…12 Ramos et al 11 compared the phenotype of SFPKS with HCS and concluded that ascertainment bias had led to the delineation of SFPKS as a distinct condition. Two additional cases of SFPKS were subsequently reported in female patients 7,13 and both authors concluded that HCS and SFPKS are likely to be allelic. Both individuals described here are heterozygous for truncating mutations in exon 34 of NOTCH2, similar to those identified in individuals with HCS.…”

“…Case one 5 was originally reported as an example of familial SFPKS, but her phenotype has evolved into a more typical HCS presentation complete with acrosteolysis. Case two 7 presented with marked serpentine fibulae and lacks acro-osteolysis, but many of her other phenotypic features were typical of the HCS phenotype. The phenotypic overlap between HCS and SFPKS was first noted in a description of a cohort of individuals with HCS and polycystic kidney syndrome.…”

“…7 She had bilateral sensorineural hearing loss. Radiographs of the patient showed wormian bones, vertebral abnormalities and serpentine fibulae.…”

“…6 Mutations in FLNA, the locus mutated in Melnick Needles syndrome, have been excluded in one individual with SFPCKS. 7 In the report of the familial instance of SFPKS, it was noted that the three siblings had significant phenotypic overlap with the autosomal dominant condition known as Hajdu-Cheney syndrome (HCS). 5 The presentation of HCS is variable but typically includes acro-osteolysis of the distal phalanges, generalised osteoporosis, craniofacial anomalies, short stature, premature tooth loss and cystic kidneys.…”