Background

Melnick-Needles syndrome (MNS, OMIM: #309350) is an extremely rare osteochondrodysplasia [1,2,3]. To date, less than 70 cases of MNS have been reported worldwide [4]. MNS is caused by gain-of-function mutations in the FLNA gene (OMIM: #30017) which encodes filamin A. Patients with MNS typically have unusual facial features, short ribbon-like ribs, scoliosis, bowing of the long bones, and vertebral scalloping [5]. Intelligence is not impaired. In more severe cases, affected individuals die in the second or third decade of life from respiratory failure secondary to the chest wall abnormalities [4].

MNS is a member of a group of five X-linked diseases with overlapping clinical phenotypes, known collectively as otopalatodigital syndrome (OPS) spectrum disorders [6]. Other members of the group are OPS type 1 (OMIM: #311300), OPS type 2 (OMIM: #304120), frontometaphyseal dysplasia (FMD, OMIM: #305620), and terminal osseous dysplasia with/without pigmentary defects (TODPD, OMIM: #300244). MNS is found almost exclusively in females, as the syndrome is lethal during gestation or the perinatal period in almost all affected males [7]. In males that do survive to term, the phenotype is clinically indistinguishable from that of OPS type 2 [8]. Females with MNS have characteristic clinical and radiologic diagnostic findings. Table 1 shows details of the clinical features of patients with MNS reported in the past 15 years [9,10,11,12,13,14].

Table 1 Summary of Melnick-Needles syndrome case reports within the past 15 years
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Because MNS is extremely rare and some cases are lethal, mostly it is detected as de novo condition, but once it is developed, it is inherited in an X-linked dominant manner [15, 16]. However, previous reports did not describe the familial characteristics of the disease in detail. In this case report, we describe a family with MNS who exhibited variable severity of phenotypic changes despite having an identical FLNA gene mutation.

Case presentation

A 16-month-old female was referred to our orthopedic department because of bowed legs and an abnormal chest X-ray. She was 80 cm (50th percentile) tall and weighed 9.7 kg (25th percentile). Her past medical history was positive for delayed physical development, as well as recurrent respiratory tract infections and episodes of otitis media. Examination revealed several facial characteristics of MNS, including prominent eyes, supraorbital hyperostosis, full cheeks, and micrognathia (Fig. 1). Plain radiographs revealed a number of abnormalities.

Fig. 1
figure 1

Photographs showing general morphology of the patient at age 16 months. a The patient’s face exhibited prominent eyes, supraorbital hyperostosis, full cheeks, and micrognathia. b Her legs and arms were thin and curved

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X-ray showed thoracolumbar kyphoscoliosis and anterior and posterior vertebral scalloping; humerus cortical irregularity with bowing; thin wavy ribs; pelvis hypoplasia of the pubis and ischium and bilateral coxa valga; bilateral bowed leg deformities, with normal epiphyses and metaphyses. The bone age estimated from X-rays of the hand was 1.5 years, which was similar with the patient’s chronological age (Fig. 2).

Fig. 2
figure 2

Plain radiographs of the patient at age 16 months. Overall, the patient’s bones were curved and thin. Bone age was not delayed, but her bones did not have normal alignment or cortical bone maturity and showed osteodysplasia. a, b, red arrow The patient had a thoracolumbar kyphoscoliosis with a humeral cortical irregularity and thin, wavy ribs. c, red circle Bilateral bowed leg deformities with Erlenmeyer flask deformity were observed. d, e The pubis and ischium were hypoplastic, and coxa valga was present bilaterally. f The ulna and radius were curved. g Bone age was normal, according to the hand radiographs

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To confirm the clinical impression of MNS, we performed genetic analyses. Target exome sequencing revealed a heterozygous mutation in the FLNA gene, c.3578 T > C, p.L1193P, which confirmed the diagnosis. Subsequently, the patient continued to have repeated respiratory tract infections and otitis media episodes. She died at the age of 6 years of a cardiac arrest, the direct cause of which was undetermined.

Target exome sequencing was also performed for all available family members. Her mother and older sister were found to have the exact same mutation, although they exhibited less severe MNS phenotypes. Her mother had full cheeks (like the patient) and lumbar scoliosis, but she had minimal leg deformities (Fig. 3). Her older sister had essentially no MNS facial characteristics, but she did exhibit coxa valga deformities (Fig. 4). When initially assessed, the sister’s spinal alignment was normal, but thoracolumbar kyphoscoliosis was observed at 9 years of age.

Fig. 3
figure 3

Photographs and plain radiographs of the patient’s mother. Overall, the patient’s mother had relatively mild deformities, when compared with the patient. a, b Like the patient, she had full cheeks and micrognathia,which were mild. c, d, e She also had mild lumbar scoliosis, kyphosis, and minimally bowed legs bilaterally

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Fig. 4
figure 4

Photographs and plain radiographs of the patient’s older sister. a, b The patient’s older sister had a nearly normal-appearing face. c, d At 6 years of age, plain radiographs revealed normal spine alignment. e However, bilateral coxa valga and Erlenmeyer flask deformities were noted at 6 years of age. f, g At age 9 years, thoracolumbar kyphoscoliosis was apparent. h The coxa valga and Erlenmeyer flask deformities were still present

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Discussion and conclusions

The locus associated with MNS is the FLNA gene, which encodes the cytoskeletal protein filamin A. FLNA comprises 48 exons and encodes a modular protein with an N-terminal actin-binding domain and a tail of 24 structurally homologous repeats [4]. Cellular functions mediated by filamin include linking signal transduction events to modulation of the actin cytoskeleton and gene transcription [17]. In 2003, Robertson et al. reported that MNS is caused by gain-of-function mutations in the FLNA gene and has an X-linked pattern of inheritance. They also noted that FLNA mutations are responsible for OPS type 1, OPS type 2, FMD, and TODPD (Table 2) [6, 12, 18].

Table 2 Comparisons of key features of OPS spectrum disorders [6, 12, 18]
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The pathogenesis of MNS has not been established. Some researchers have reported increased skeletal collagen content, which could explain the sclerosing bone process [9]. Fryns et al. suggested that MNS was a generalized connective tissue disorder because of the hyperlaxity of skin and joints [19]. Urological, pulmonary, and cardiac involvement is also common in patients with MNS [20, 21]. Although diverse phenotypes may occur [22], affected females are usually short and may have delayed motor development, osteoarthritis, a hoarse voice, and urethral stenosis (leading to hydronephrosis), in addition to the main abnormalities [1].

It is not yet known why phenotypes may differ between females with MNS. Skewed X-inactivation and somatic mutation have been suggested as potential mechanisms [23, 24]. For example, Robertson et al. reported monozygotic twin sisters, only one of whom had MNS [24]. In our case, although phenotypic severity differed between female family members, they all had the same heterozygous FLNA mutation (c.3578 T > C, p.L1193P). Interestingly, the mutations identified in this family have not been previously reported in the National Center for Biotechnology Information’s ClinVar. As mentioned earlier, pathogenesis of MNS has not been established well. Further research is also needed to determine pathogenicity of this mutation among these families with MNS.

It should be noted that the patient with MNS would demonstrate the typical bone deformity in the distal femur, which was called as the Erlenmeyer flask deformity like Camurati-Engelmann disease (CED, OMIM: #131300). CED is another rare genetic skeletal disorder caused by tumor growth factor-β1 mutation, which is characterized by limb pain, muscle emaciation and weakness, cortical thickening of the diaphysis of long bones, and also Erlenmeyer flask deformity [25, 26].

Although MNS is rare, physicians should be aware of the disorder, including its variable manifestations, because of the potential lethality of severe disease. A possible hereditary mutation should be suspected even when family members have an almost normal appearance. Thus, in patients exhibiting traits suggestive of MNS, imaging studies and genetic testing should be performed for both the patient and all family members.

Informed consent statement

Informed written consent was obtained. It contains publication of this report and the accompanying images, including photographic rights of patient, her mother and her sister (Use of medical information for academic purposes, including the portrait rights shown in Figs. 1, 3 and 4). For the patient, her mother and her sister, written consent was obtained from the father and mother for all teaching and academic purposes, including publication of this case report.