A rare type of localized gigantism known as macrodystrophia lipomatosa is characterized by a disproportionate increase in fibroadipose tissues and a gradual overgrowth of all mesenchymal elements. The distribution in the lower extremities' plantar nerves and the upper extremity's median nerve is most commonly observed. This abnormality is congenital and typically manifests at birth or during the neonatal stage. This deformity begins to mechanically impair joint function, blood supply, and innervation as age advances. The findings from radiography include lucencies in the soft tissues and expansion of the digit's phalanges and soft tissue components, with predominantly distal component involvement. Herein, we present a case of a 20-year-old male from rural India who came to us with the complaint of abnormal asymmetrical swelling of bilateral hand fingers, which has been progressing since birth. Physical examination revealed a soft, non-fluctuant, non-pulsatile swelling with no associated trauma or injury. The clinical picture revealed disproportionate enlargement of phalanges in both hands.

Lipomatosis of peripheral nerves (LPN, also known as fibrolipomatous or lipofibromatous hamartoma of peripheral nerves) is a very rare, benign, intraneural, tumorous lesion that predominantly involves the median nerve but may rarely affect any peripheral nerve. Recently, PIK3CA mutations have been reported in macrodactyly, a rare condition related to LPN, and in other localized lipomatous overgrowth syndromes. In this retrospective study, we report 6 cases of FPN involving the median nerve (4 of them identified among 570 patients with carpal tunnel syndrome who underwent surgical decompression at our center from 2012 to 2022 and two seen in consultation by one of the authors). All cases were diagnosed via biopsy or resection supplemented by MRI. Patients were 4 males and 2 females aged 23 to 60 years (mean 38 years). One patient with bilateral lesions had in addition extensive angiomatosis of the paravertebral region. Histological examination showed an abnormal amount of mature fatty tissue containing disordered fibrous bands, entrapping normal-looking nerve fibers with prominent perineurial and endoneurial fibrosis. Genetic analysis using snapshot assay constructed to detect hotspots mutations in PIK3CA revealed similar PIK3CA mutations (p.H1047R; c.3140A>G) in 5/6 cases (83.3%). Our study represents a further contribution to the literature on LPN and highlights the diagnostic value of PIK3CA mutation testing as surrogate tool in equivocal cases and in those lesions without associated macrodactyly, especially as the biopsy findings of this lesion are essentially nonspecific.

A 20-yr-old man with Proteus syndrome (PS) and somatic mosaicism of the AKT1 c.49G > A p.(E17K) variant had asymmetric overgrowth of the right frontal and facial bones, asymmetric spinal overgrowth with thoracolumbar scoliosis, dilatation of the inferior vena cava, testicular cystadenoma, bilateral knee deformities, macrodactyly, and apparent intellectual disability. Miransertib (ARQ 092) is an oral, allosteric, selective pan-AKT inhibitor initially developed for cancer therapeutics, now being evaluated for the treatment of PS. After baseline evaluation, the patient started unblinded treatment of 10 mg oral miransertib daily (∼5 mg/m2/day), escalated to 30 mg daily (∼15 mg/m2/day), and then to 50 mg daily (∼25 mg/m2/day) after 3 mo of treatment. Adverse events included dry mouth, one episode of gingivostomatitis, and loose, painful dentition due to preexisting periodontal disease, all of which resolved spontaneously. After 11 mo of treatment, the patient reported improved general well-being, increased mobility of the ankle, spine, and hands, a subjective decrease in size of the right facial bone overgrowth, and reduced areas of cerebriform connective tissue nevi on the soles. Whole-body MRI findings were stable without apparent disease progression. We conclude that 1 yr of treatment with miransertib was beneficial in this case.

Fibrodysplasia ossificans progressiva (FOP), an ultra-rare and disabling genetic disorder of skeletal malformations and progressive heterotopic ossification, is caused by heterozygous activating mutations in activin A receptor, type I/activin-like kinase 2 (ACVR1/ALK2). The rarity of the disease makes it common to make a misdiagnosis and cause mismanagement. We reported a case of a sixteen-year-old male patient who had suffered from pain and swelling in the biopsy site for two months. His physical examination presented serious stiffness and multiple bony masses in the body, with his bilateral halluces characterized by hallux valgus deformity and macrodactyly. Imaging examinations showed widespread heterotopic ossification. All laboratory blood tests were normal except for the one on alkaline phosphatase. A de novo heterozygous mutation (c.617G > A; p.R206H) were found in the ACVR1/ALK2 using gene sequencing. Even though FOP is a rare disorder of genetic origin, which is generally misdiagnosed, the genetic analysis could provide definitive confirmation of the disease. Awareness of such an important approach can help clinicians to avoid the commonly practiced misdiagnosis and mismanagement of the rare disease.

Macrodactyly in the context of tuberous sclerosis complex (TSC) is a known but rare manifestation. We report the case of a boy diagnosed with TSC at 2 years and 4 months of age, presenting with bilateral macrodactyly of the first three fingers of both hands, with underlying radiographic changes, in whom molecular analysis identified a frameshift mutation on the TSC1 gene (encoding hamartin), leading to a premature stop codon. We reviewed the literature for reported cases of TSC patients with the same manifestation. In four of 14 patients, including ours, macrodactyly caused some type of joint limitation or flexion deformity, thus contradicting the established idea that this is a finding without clinical significance. Our patient is, to our knowledge, the first reported to have clear bilateral involvement. We briefly discuss the underlying mechanism for this phenomenon, which has yet to be fully elucidated, although somatic mosaicism for loss of heterozygosity at TSC loci is a plausible explanation. © 2016 Wiley Periodicals, Inc.