Acromicric dysplasia with stiff skin syndrome‐like severe cutaneous presentation in an 8‐year‐old boy with a missense FBN1 mutation: Case report and literature review

Abstract Background Acromicric dysplasia is a rare heritable short‐stature syndrome with joint stiffness and varying degrees of cutaneous hardness. Stiff skin syndrome is a rare connective tissue disorder characterized by diffusely thick and hard skin from the time of birth. Heterozygous point mutations in the FBN1 have been proposed as the predominant cause of both diseases. Methods By performing skin biopsy, X‐ray imaging, electrocardiography, as well as whole‐genome sequencing and Sanger sequencing, we diagnosed an 8‐year‐old Chinese boy as acromicric dysplasia with severe skin stiffness caused by a heterogeneous mutation in the FBN1. Results The patient presented with skin tightness, wrist and ankle stiffness, short stature and limbs, several deformed joints in the extremities, cone‐shaped epiphyses, and distinct facial features. He also had a patent foramen ovale and frequent respiratory infections. Skin biopsy showed thickened dermis and excessive collagen aggregation. Alcian blue staining indicated dermal mucopolysaccharide deposition. Mutation analysis revealed a heterozygous missense mutation, c.5243G>A (p.Cys1748Tyr), in exon 42 of the FBN1. Conclusion This is a report about acromicric dysplasia with stiff skin syndrome‐like severe cutaneous presentation caused by a single hotspot mutation, further revealing the gene pleiotropy of FBN1.

metacarpals. Facial abnormalities are often mild, characterized by round face, long eyelashes, bulbous nose with upturned nostrils, prominent philtrum, and thick lips with a small mouth. Frequent bronchopulmonary infections associated with tracheal problems and carpal tunnel syndromes have also been reported in some patients (Le Goff et al., 2011). Skin stiffness was seen in some of the patients, but its presentation and severity has not been well defined. Most reported patients only showed mild phenotype, but severe cases also existed. What is more, mucopolysaccharides could also accumulate in the patient's dermis, making it hard to differentiate from another genetic disease named stiff skin syndrome (Spranger, Gilbert, Tuffli, Rossiter, & Opitz, 1971). Until 2016, all heterozygous point mutations of FBN1 resulting in AD were exclusively located in exons 41 and 42 (Sakai, Kenne, Renard, & Backer, 2016). LTBP3 was also reported to play an etiological role in AD, but the pathomechanism behind this has remained unclear (Intarak et al., 2019).
Stiff skin syndrome (SSS) (OMIM #184900) is a rare congenital connective tissue disorder with complete penetrance. It is characterized by diffusely thickened and indurated skin from the time of birth, which limits joint mobility with flexion contractures. Some other less common features include cutaneous nodules affecting extension and flexion of the distal interphalangeal joints, and relatively short stature (Loeys et al., 2010). Histopathological assessments showed excessive aggregations of thickened collagen bundles at the dermal-epidermal junctions. Alcian blue staining was usually positive, indicating the presence of mucopolysaccharide in patients' dermis (Geng et al., 2006;Loeys et al., 2010). Exon 37 of FBN1 is the hotspot for heterozygous point mutations leading to SSS (Loeys et al., 2010).
Here, we report an 8-year-old Chinese boy diagnosed as AD related to a single heterozygous missense mutation, c.5243G>A (p.Cys1748Tyr), in exon 42 of the FBN1. What makes him even more special is the severe hard skin presentation. Another point mutation at the same site was reported as causing Weill-Marchesani syndrome (Cecchi et al., 2013). This article helps further illustrate the pleiotropism of FBN1 and highlight the skin stiffness as a significant feature of AD.

| Ethical compliance
This study was performed under the guidance of the principles of the Declaration of Helsinki. The family provided informed consent and understood that all patient samples would be used for research and genetic counseling. All regulations regarding patient enrollment, sample collection, and informed consent for the purposes of this research were followed.

| CLINICAL REPORT
An 8-year-old boy was admitted to our clinic for hard skin all over the body and short stature, which had been present for more than 7 and 5 years, respectively (Figure 1a relevant family history. His mother suffered from colds four to five times during pregnancy. Apart from some Chinese herbal medicines with no teratogenic effects reported, no other medication history was mentioned. The perinatal condition was unremarkable, with birth weight of 3.5 kg (normal) and body length of 50 cm (normal). From the time of birth, skin tightness and wrist and ankle stiffness were noted (Figure 1c, d). At the age of 1 year and 3 months, short stature was noted. Skin biopsy showed mild epidermal keratosis, increased basal layer pigmentation, thickened dermis, and excessive deposition of collagen and elastin (Figure 2a, b). Alcian blue staining indicated mucopolysaccharide deposition in the dermis (Figure 2c). Since his symptoms occurred at an early age, while collagen aggregation and mucopolysaccharide deposition appeared at the same time, systemic sclerosis and scleredema could be excluded. Sclerema neonatorum was not considered because no acicular crystals were found in adipocytes. Nevertheless, only based on clinical manifestation and pathological results, SSS could not be ruled out. At the time of consultation, his skin thickening had been under little remission for 1 year without medication, although the reason for this was unknown. We inferred that environmental factors, such as food or clothes, might play a role in this transient improvement. However, the skin condition remained unchanged after then. As for the short stature, his body weight was 16.5 kg (<−3SD) and height was 99.5 cm (<−3SD). Bone age was estimated to be only 5 years old. Short limbs, cone-shaped epiphysis of forearms and legs, significant genu varum, and deformed ankles, wrists, and interphalangeal joints, as well as brachydactyly were also noted (Figure 3a, b). There was also pronounced soft-tissue swelling around the elbow. In addition, the patient had facial features including epicanthus, hypotelorism, and a depressed nasal bridge. Electrocardiography examination revealed patent foramen ovale. Frequent respiratory infections were also reported. Lens examination and other baseline investigations, including thyroid and function tests, appeared to be normal. Whole-genome sequencing and Sanger sequencing were performed on genetic DNA extracted from the peripheral blood of the patient. The results indicated a heterozygous missense mutation, c.5243G>A (p.Cys1748Tyr), in exon 42 of the FBN1 (Figure 3c). According to this specific mutation site, we finally excluded SSS.
In conclusion, with the clinical manifestations and the substitution C1748Y, after ruling out SSS, we diagnosed this patient as having AD with extraordinarily severe skin hardness. For treatment, he was injected with recombinant human somatropin. Although no increase of IGF-1 has been identified at the time of writing, no effect on bone growth has also yet been seen.

| DISCUSSION
The FBN1 (OMIM #184900) encodes a large cysteine-rich modular-secreted glycoprotein named fibrillin-1. Its key component structures are 7 eight-cysteinemotifs, which exhibit homology to latent TGFβ binding proteins. Principally, by recruiting ADAMTS superfamily proteins as binding proteins, fibrillin-1 is crucial for microfibril formation and regulation (Wang, Zhang, Ye, Han, & Gu, 2014). Although the causative mechanisms of both AD and SSS remain unclear, they are believed to be related to microfibrillar malformations or dysfunctions.
AD is a rare autosomal dominant disorder, which belongs to the acromelic dysplasia group of conditions. In terms of causative mutations of AD, these were predominantly limited to mutations in exons 41 and 42 of FBN1 (Table 1). However, FBN1 mutations in these two exons might also cause another two short-stature syndromes, termed geleophysic dysplasia (GD) and Weill-Marchesani syndrome (WMS) (Cecchi et al., 2013). Although these three diseases share common features, such as short stature and brachydactyly, they can still be differentiated by other features. For example, WMS patients usually present eye anomalies, including microspherophakia, ectopia lentis, glaucoma, cataracts, and myopia, which seldom appear in AD patients (Table 1) (Faivre et al., 2003). GD is more severe than AD, with additional features including tracheal stenosis and symptomatic cardiac involvement leading to early death (Jin et al., 2017). Because our patient's symptoms, especially the congenital heart disease, were milder, and he showed no eye anomalies, GD and WMS could be ruled out. Interestingly, c.5242T>C (p.Cys1748Arg) has previously been reported to cause WMS (Cecchi et al., 2013). However, the mechanism underlying this allelic condition was unclear.
Microfibrils are abundant in the extracellular matrix of the growth plate, especially in the resting and proliferative zones (Yu & Urban, 2013). TB5 domain, encoded by exons 41 and 42, has been demonstrated to interact with heparin via two