Early onset mandibuloacral dysplasia due to compound heterozygous mutations in ZMPSTE24

Abstract

Mandibuloacral dysplasia (MAD) is an autosomal recessive disorder characterized by hypoplasia of the mandible and clavicles, acro-osteolysis, and lipodystrophy due to mutations in LMNA or ZMPSTE24. Only six MAD patients are reported so far with ZMPSTE24 mutations and limited phenotypic data are available for them. Here, we report on two brothers (4 years and 9-month old) with early onset MAD due to ZMPSTE24 mutations in whom thin skin was noted as early as 5 months of age. Both had micrognathia, mottled hyperpigmentation, and enlarged fontanelles but little evidence of lipodystrophy. There was no delay of mental development. The older brother had small pinched nose, short clavicles, acro-osteolysis, stunted growth, joint stiffness, and repeated fractures. There was no evidence of renal disease. Both patients were compound heterozygotes harboring a previously reported missense ZMPSTE24 mutation, p.Pro248Leu, and a novel null mutation, p.Trp450stop. These patients and the review of literature reveal that compared to MAD patients with LMNA mutations, those with ZMPSTE24 mutations develop manifestations earlier in life. Other distinguishing features in MAD due to ZMPSTE24 mutations may include premature birth, renal disease, calcified skin nodules, and lack of acanthosis nigricans. We conclude that in patients with MAD due to ZMPSTE24 mutations, the onset of disease manifestations such as thin skin and micrognathia occurs as early as 5 months of age. In these patients, skeletal phenotype presents earlier whereas lipodystrophy and renal disease may occur later in life.

Figure 1

Clinical Features of Patient MAD4700.3. A, The patient has a small nose with telangiectasias, prominent cheeks, prominent superficialveins, low-set ears, micrognathia, and slight double chin. B, Bulbous appearance of distal fingers consistent with acro-osteolysis. C, Radiograph of the hand at 13 months showing irregularity of the tufts of all terminal phalanges, consistent with acro-osteolysis. D, Lateral view of the patient showing near normal body fat distribution and lack of overt lipodystrophy. E, Dry, straight, bright red hair with areas of hair thinning and alopecia particularly on the back of scalp and on the left parietal and frontal region. F, Computerized tomography of the head at 7 months with 3-Dreformations showing multiple Wormian bones in both lambdoid sutures. G, Mottled pigmentation in the abdomen and inguinal areas.

Figure 2

Clinical Features of Patient MAD4700.4. A, B, The patient has low-set ears, prominent cheeks, and micrognathia. Skin on the face was thin and superficial veins were seen on the forehead. No hair loss from the scalp, eyebrows or eyelids. C, Mottled pigmentation in the abdomen and inguinal areas. D, Base of the fingers appeared slightly bulbous but there were no overt signs of acro-osteolysis. E, Normal appearance of the toes.

Figure 3

Onset of disease manifestations in ZMPSTE24 MAD/Progeria-like cases. Each patient is represented by a different symbol.