PMC9436604_01
Clinical features, radiological examination findings, and genetic analysis results of our patient. (a-f) Clinical features of our patient at the first visit to our hospital. Left (L); right (R). (a) General appearance. Thin eyebrows, low-set ears, hypoplastic mandible, narrow chest, and shallow umbilicus were observed. (b) Hands. Incomplete syndactyly was observed in both hands. All fingers lacked nails. (c) Feet. Incomplete syndactyly was observed in both feet. All toes lacked nails. (d) Right ear. The lower part of the ear was hypoplastic. A periauricular sinus (arrow) was observed. (e) Flare-up observed at the occipital region of her head (arrow). The hair was sparse. (f) Flare-up observed at her back (arrow). (g-l) Results of radiological examinations. Left (L); right (R). (g) Roentgenograph of the hands at 7 months of age. Agenesis of all distal phalanges, second and fourth middle phalanges, and fifth metacarpal bone, fusion of enlarged first middle metacarpal bone and proximal phalange (arrows), shortened second and fourth metacarpal bones, and proximal phalanges (closed arrowheads), and hypoplasia of the fifth middle phalanges and metacarpal bones (open arrowheads) were observed. Osteochondromas were observed in both first fingers. (h) Roentgenograph of the feet at 2 years of age. Thick first metacarpal bones (arrows) and fused left fourth and fifth metacarpal bones were observed (closed arrowheads). (i) 3D CT analysis at 7 months of age. The left sternocleidomastoid muscle was ossified (arrow). Craniosynostosis was not observed. (j-l) Head CT analysis at 6 years of age. (j) Horizontal view. The septum pellucidum was lacking. The lateral ventricle was enlarged. (k) Sagittal view. The corpus callosum was thin, and a deformed brain stem with bulging dorsal pons was observed. (l) Coronal view. Not only the lateral ventricle but also the third ventricle was enlarged. The sylvian fissure was wide. (m) Results of the genetic analysis of the patient and her parents. A heterozygous base substitution from adenine to guanine at position 772, resulting in an amino acid change from arginine to glycine at 258, was observed in the patient (arrow). This substitution was not observed in either of her parents. Forward strand (F); reverse strand (R).
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Her multiple congenital anomalies included soft tissue syndactyly of the hands and feet without nails, low-set ears, auricular anomaly, and hypoplastic mandible (Figures 1(a)-1(d)). At the first visit to our hospital, small malformed teeth, thin eyebrows, shallow umbilicus (Figure 1(a)), and sparse hair (Figure 1(e)) were observed in addition to the anomalies found at birth. Radiologic analysis revealed multiple symmetrical abnormalities of the phalanges and metacarpal bones in the hands and feet and heterotopic ossification of the sternocleidomastoid muscle (Figures 1(g)-1(i)). Head CT analysis at 6 years of age revealed enlargement of the lateral and third ventricles, which was not progressive, lack of septum pellucidum, hypoplastic corpus callosum, and deformed brain stem including bulging dorsal pons (Figures 1(j)-1(l)). As a result, a heterozygous single base substitution, c.772 A > G, in the coding region of ACVR1, resulting in p.Arg258Gly, was identified in our patient, while other known pathogenic variants, including p.Arg206His, were absent (Figure 1(m)).
Time-course series of heterotopic ossification (HO). (a-d) Front chest and upper limbs. (e-h) Back chest. (a, e) At 10 months of age, HO was not observed. (e) Cervical vertebrae fusion was observed. (b, f) At 26 months of age, HO was observed from the bilateral axillary and humerus. (c, g) At 42 months, HO was observed between the humerus and radius and between the humerus and thoracic cage. (d, h) Scoliosis due to multiple HO occurrences was observed at 106 months. (i-m) Lumbar spine and pelvis. (i) At 26 months of age, HO was not observed. (j) At 42 months of age, HO was observed from the left transverse process of the lumbar spine. (k) At 78 months of age, HO was observed from the neck of the left femur and connected the left transverse process and left femur thereafter. (l) At 106 months of age. (m) At 121 months of age.
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However, heterotopic ossification following the frequent flare-ups was not suppressed (Figure 2).