Mandibuloacral dysplasia type A-associated progeria caused by homozygous LMNA mutation in a family from Southern China

The studies were approved by the Institutional Review Boards of the First Affiliated Hospital, Sun Yat-sen University, China, and written informed consent for the patients obtained from their parents, and consent for the parents signed by themselves.

Patient 1, belonging to a non-consanguineous parents, was a 7-year old Han Chinese girl. She was born full-term with a birth weight of 2.4 kg and a length of 48 cm, and did not exhibit any abnormalities until the age of 10 months, when her upper limbs were noted with mottled hyperpigmentation, which progressed gradually associated with sclerodermatous change thereafter. At the age of 12 months, her parents noticed that she had swelling of hands and fingers with decreased mobility, and had decreased scalp hair growth (Figure 1), and failed to thrive. She had her first walk at the age of 14 months. At the age of 22 months, finger joints became painful and stiff. At the age of 26 months, similar mottled hyperpigmentation, thin skin and sclerodermatous change presented over the lower limbs and hips; and stiff feet joints were present; those made the girl have limited activity. All the symptoms progressed slowly. At her age of 30 months, based on the biopsy and laboratory test results, she was diagnosed as scleroderma, and was treated with prednisone 10 mg daily in combination with Chinese medicine, the steroid was then tapered gradually and had lasted for more than 2 years till the end of treatment. During the treatment, the cutaneous lesions progressed slowly associated with appearing of a bird-like face with beaked nose and bulbous cheeks, swallowing difficulties and thin skin, only the joint stiffness had mild improvement. Since the age of 5 years, carious and ragged teeth and hair alopecia including loss of eyebrow appeared. She also developed swallowing difficulty with frequent vomiting or choking, especially when drinking water. Defecating difficulty with frequent anal fissure were noted as well.On examination, her weight (9 kg), height (95 cm), and head circumference (45.5 cm) were below the normal range (<mean-3 standard deviation (SD), all were below the third centile). She showed an extremely short stature, and distinctive face with diffuse scalp hair loss and decreased eyebrow, prominent scalp veins, bulbous cheeks, tapered nasal tip, irregular teeth and lower jaw dental crowding, and mandible hypoplasia (Figure 2A-E). She had loss of subcutaneous fat over the entire body, and mottled pigmentation and sclerodermatous changes over her trunk and lower limbs with protuberant abdomen and easily visible veins on abdomen (Figure 2F-G). She had thickened skin on heels and around the ankles (Figure 2A-C), and had a varus deformity of the knees with wide-based gait and shuffling. Severe contractures at the interphalangeal joints and the hands with marked finger tip rounding and nail atrophy had resulted in flexion deformity of fingers, and decreased mobility (Figure 2H, I). Mild elbow and knee contractures were also observed, but no spine rigidity was present. She had mild weakness of neck muscles with somewhat dropping head. She was absent for circumoral cyanosis. Her mental development including calculation was normal.

Complete hemogram, erythrocyte sedimentation rate, urine examination, liver and renal function tests, serum glucose and phosphocreatine kinase were within normal limit. The serum CK-MB was 36 U/L (normal range: 0 ~ 25 U/L). The serum lipid profiles showed a decrease in high density lipoprotein cholesterol (0.93 mmol/L, normal range: 1.09-1.63 mmol/L) with the other parameters being normal. X-ray findings of extremities showed lower skeletal density, flexion deformity of fingers, and delayed bone age with absence of the lesser multangular bone, the great multangular bone, and the scaphoid bone (Figure 2J). Radiological changes in chest revealed pyriform thorax, absence of clavicles, and absence of posterior parts of the 2^nd and 3^rd ribs on both sides, and thin posterior parts of the 4^th to 6^th ribs on left side and the 4^th on right (Figure 2K). However, the chest scan of computed tomography showed normal clavicles 4 years ago (Figure 2L). B-ultrasonic showed loss of the subcutaneous fat. Electromyogram for the extremities showed normal conduction velocity and normal wave. Repeated electrocardiograms showed normal.

Patient 2, the younger sister of patient 1, was 3-year- and 3- month-old. She was delivered after an uneventful pregnancy at 34 weeks of gestation (length: 45 cm; weight: 1.8 kg). She showed normal motor and mental development since the birth, and the growth was regular until she was noted sequently to have growth retardation, mottled hyperpigmentation, cutaneous sclerodermatous change, thin skin, decreased subcutaneous fat and joint stiffness at the age of 12 months. The symptoms developed gradually, but her parents noticed that all her symptoms progressed more rapidly than her older sister’s. Thereafter, progressive loss of hair and eyebrows, swallowing difficulty and bulbous cheeks were present slowly. She also complained that water-drinking may make her choke with ease. She had her first walk at the age of 18 months.The examination showed her weight (7.5 kg), length (79 cm) and head circumference (44.3 cm) were below the normal range (<mean-3SD, below the third centile), with a senile appearance (Figure 3A-C). She had hyper- or hypo-pigmentation, sclerodermatous changes and thin skin on the lower abdomen, buttocks, elbows and the lower extremities (Figure 3A-C). Sparse scalp hair with easily visible veins was present (Figure 3D). Irregular and carious teeth, and crowded teeth on the mandible were also observed (Figure 3E,F). Lipodystrophy on gluteal region, extremities (Figure 3B,C) and palmoplantar areas was noted. Severe contractures at the interphalangeal joints and the hands with marked finger tip rounding had resulted in abnormal posture and decreased mobility (Figure 3G,H). Her nails were mildly dystrophic. There was coarse and thickened skin on the back of hands, around the ankles and on the heels in symmetry (Figure 3I). Her gait was waddling. No circumoral cyanosis was present. Her mental development was normal. Repeated electrocardiograms showed normal.

The laboratory tests including biochemistry (including serum phosphocreatine kinase) and lipid profiles were normal or within normal limit, except an increase of serum CK-MB (56 U/L, normal range: 0 ~ 25 U/L) and a decrease of high density lipoprotein cholesterol (0.68 mmol/L, normal range: 1.09-1.63 mmol/L). X-ray findings of extremities showed flexion deformity of fingers of hands and delayed bone age (Figure 3J). Radiological changes in chest revealed pyriform thorax as her elder-sister presented, absence of right clavicle, and absence of mid-lateral part with thin interior part of left clavicle, and thin posterior parts of the 2^nd and 3^rd ribs on both sides with disconnection of posterior parts of the 3^rd rib on left side and the 2^nd and 3^rd on the right (Figure 3K). B-ultrasonic showed the thickness of subcutaneous fat was 4 mm on the involved areas of both thighs. Electromyogram for the extremities showed possibility of myogenic damage.

Patient 3, the youngest sibling in the pedigree, was a 10-month-old boy. He was also delivered after an uneventful pregnancy at 37 weeks of gestation (length: 48 cm; weight: 3.2 kg). He was noticed hypermyotonia and swelling of lower extremities at the age of 8 months with gradual progression. His parents noticed that his lesions were more severe and progressed more rapidly than both sisters did. His motor and mental were normal at the time.Examination showed his weight (7.7 kg) and height (68 cm) were below the normal range (<mean-2SD, below the third centile), and the head circumference (44.5 cm) was in normal range (equal to the twenty centile). His lower extremities were found swelling with mild hyperpigmentation (Figure 4A), and increase of muscular tension. Decreased scalp hair with prominent scalp vein (Figure 4B) and mild contractures at the interphalangeal joints of hands were also noted (Figure 4C). No other abnormalities including circumoral cyanosis were observed at the time. The laboratory tests including biochemistry and lipid profiles were normal or within normal limit, except increase of lower-density lipoprotein cholesterol (4.00 mmol/L, normal range: 1.94-3.61 mmol/L), serum CK (579 U/L, normal range: 250–200 U/L) and CK-MB (80 U/L, normal range: 0 ~ 25 U/L). The parents refused to take muscle biopsy. X-ray findings of the hands showed acro-osteolysis and thorax X-ray including clavicle and ribs showed normal (Figure 4D,E). Thickness of subcutaneous fat was 11 mm on the involved areas of both thighs. Electromyogram for the extremities showed possibility of myogenic damage.

In a phone follow-up during the manuscript was being revised (the patient was 1-year and 10-month old at the time), his mother reported that his mental was still normal, and his first walk began at his age of 14 months; all his symptoms developed more rapidly than his elder sisters did, and mildly progressive contractures of knee joints appeared recently which made him have limited activity.

Their mother was a 42-year-old Han Chinese woman with healthy appearance (length: 152 cm, weight: 50 kg). Her radiological changes in chest and laboratory tests including biochemistry and lipid profiles were normal or within limit, except for increased lower-density lipoprotein cholesterol (4.06 mmol/L, normal range: 1.94-3.61 mmol/L). She had no abortion. Their father was a 41-year-old Han Chinese man with normal appearance (length: 170 cm; weight: 70 kg). His chest x-ray and laboratory tests were also normal or within normal limit, except decreased high-density lipoprotein cholesterol concentration of 0.80 mmol/L and increased lower-density lipoprotein cholesterol concentration of 4.19 mmol/L. Both fasting glucose and 2-hour postprandial blood glucose of the parents were normal.

Genomic DNA was isolated from peripheral blood with a DNA isolated kit (Aidelai, CN)) according to the manufacturer’s protocol. Direct sequencing of the entire coding region and the surrounding intron-exon boundaries of the LMNA, ZMPSTE24 and BANF1 genes were conducted in the proband (the oldest sister of this pedigree). Primers of LMNA ZMPSTE24 and BANF1 genes were designed by primer3.0 software. The PCR reaction was assembled in a 25 μl reaction volume, containing 50 ng genomic DNA, 5 pmol of each primer, 1x Taq mix (Aidelai, CN). PCR was conducted on ABI 9800 using the touchdown cycle protocol modified as followed by a 3-step cycle (95°C, 5 min, 95°C, 45 s, 59°C, 45 s, 72°C, 45 s, 2cylces, 95°C, 45 s, 57°C, 45 s, 72°C, 45 s, 2cylces ; 95°C, 45 s, 55°C, 45 s, 72°C, 45 s, 2cylces; 95°C, 45 s, 53°C, 45 s, 72°C, 45 s, 30cylces; 72°C, 10 min). The PCR product was purified to remove primers and dNTPs and sequenced using ABI Prism 3100 (Perkin-Elmer Applied Biosystems, Foster City, CA). Sequence of PCR products was analyzed with Chromas 2.22.

The Genbank (http://​www.​ncbi.​nlm.​nih.​gov/​gquery/​gquery.​fcgi) accession number for the complete canine LMNA DNA sequence is NG_008692, The Genbank accession number for the LMNA mRNA sequence is NM_005572. The Genbank accession number for the ZMPSTE24 DNA sequence is NG_008695, The Genbank accession number for the BANF1 DNA sequence is NG_031874.

Written informed consent was obtained from the patient’s parents for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.