Skin Hardening and Eczema in a 9-month-old Girl

A 9-month-old girl is brought by her parents for an initial pediatric dermatology consultation for presumed atopic dermatitis. The parents report subtle "hardening" of the skin of the abdomen and lower legs since birth associated with an overlying rash previously diagnosed as eczema. The patient had normal prenatal genetic testing, newborn hearing, and metabolic screens but was diagnosed as having mild motor and speech developmental delay at her 9-month evaluation. She was previously found to have poor weight gain that has since improved. The patient's ability to sweat is intact, and she does not have dryness of her eyes or mucous membranes. Her current growth parameters include a height of 28.25 in (71.76 cm) (71st percentile), weight of 16 lb 9 oz (7.42 kg) (21st percentile), and head circumference of 17.7 in (45 cm) (79th percentile). She takes no medications. There is no family history of skin disorders or consanguinity.Her physical examination is notable for induration of her anterior legs and lower abdomen associated with fine erythematous scaly papules and plaques (Fig 1A). Prominent veins are present across the chest, abdomen, and forehead (Fig 1B). The skin is taught and translucent appearing. The patient has sparse body hair and eyebrows, in addition to sparse hair on the scalp with localized baldness on the occiput. Examination of the head and neck is notable for a broad forehead, round facies with full cheeks, microretrognathia, and a narrow nose with a slightly squared tip (Fig 2A). No teeth are present on oral examination. Her skin examination does not reveal petechiae, jaundice, or rashes. Her weight is in the 17th percentile.This 9-month-old infant with mild developmental delay presents with skin induration and dimpling. A differential diagnosis for pediatric skin hardening includes morphea, stiff skin syndrome, juvenile systemic sclerosis, harlequin ichthyosis, and Hutchinson-Gilford progeria syndrome (HGPS), as presented in the Table. (1)(2)(3)(4)(5)Of note, the patient was referred to us for eczema. An eczematous cutaneous eruption results from epidermal changes, eg, edema/swelling between keratinocytes and visualizable scale. This contrasts with induration, which is due to changes in the dermis manifesting as palpable skin hardening. Morphea is the most common cause of skin hardening, presenting with erythematous to violaceous plaques in early cases and yellow to white plaques with a violaceous border in later stages. There are several variants of morphea with characteristic distributions, including limb or medial forehead involvement. In this patient, lesions were shiny, nonerythematous plaques on the lower trunk and extremities, making a diagnosis of morphea less likely.Stiff skin syndrome is another diagnosis we considered as a cause of our patient's skin hardening; however, it was not favored in this case because it typically leads to stone-hard induration on the thighs, buttocks, hips, or shoulders. Lesions of stiff skin syndrome may also have associated hyperpigmentation and hypertrichosis, which were not present in our patient. We also considered juvenile systemic sclerosis, which can result in skin induration along with Raynaud phenomenon, sclerodactyly, telangiectasias, and calcinosis. However, these features were not appreciated here. Harlequin ichthyosis represents a dermatologic condition in which the skin is thickened, excessively scaley, and divided by deepened fissures. There is characteristically involvement of the nose, ears, mouth, eyelids, hands, and feet. Given the presence of skin hardening with lack of scale in our patient, we did not favor a diagnosis of harlequin ichthyosis.In addition, we considered the diagnosis of anhidrotic ectodermal dysplasia, which may present with chronic eczema, dry mucous membranes, hypotrichosis, hypodontia or adontia, and hypohidrosis or anhidrosis. Associated facial abnormalities include frontal bossing, lip eversion, flattened nasal bridge, or sunken cheeks. (6) However, this diagnosis does not account for skin hardening or prominent veins, and the dental and mucosal abnormalities were not present in our patient. In addition, other than frontal bossing, the associated facial features did not align with our patient's presentation.Last, HGPS was considered with highest suspicion on our differential diagnosis due to its ability to unify multiple features found on our patient's examination. HGPS most commonly involves shiny plaques on the lower trunk and extremities and is accompanied by the presence of hair loss, prominent veins, and abnormal facial features, including frontal bossing and a thin, "beaked" nose. These features were present in our patient and not accounted for by any other diagnosis.In the setting of an infant presenting with skin hardening and abnormal facies, there was a strong clinical concern for a syndromic etiology. Due to the unique signs of sclerodermoid skin, prominent veins, and alopecia, HGPS was favored as the unifying diagnosis. The patient was referred to genetics and underwent LMNA gene sequencing. Her gene sequencing was positive for LMNA c.1824C>T, confirming the diagnosis of classic HGPS.HGPS has a prevalence of 1 in 20 million people and leads to rapid aging. (7) The condition is caused by a de novo autosomal dominant mutation in the LMNA gene that encodes lamin A and lamin C proteins. Lamins are components of the nuclear membrane that help maintain the structural integrity of the nucleus. Patients with classic HGPS have a point mutation (c.1824C>T) that results in formation of a dysfunctional pre–lamin A protein, or progerin. Progerin disrupts cellular functions, which ultimately leads to premature aging. (7) The average lifespan for patients with HGPS is approximately 14.5 years. Complications of accelerated atherosclerosis are the most common cause of death. (8)Dermatologic manifestations may be the first signs of HGPS and include sclerodermoid skin changes, prominent scalp and body veins, circumoral cyanosis, and dyspigmentation (Fig 3). Affected children can appear clinically normal or present with dermatologic findings at birth. (5)(7)(8) A published review of patients with HGPS born at a single institution between 2007 and 2010 by Rork et al (5) found that all patients had at least 1 dermatologic abnormality by 2 years of age. The mean time to onset of the dermatologic manifestations presented in their study is depicted in Fig 3. Sclerodermoid skin changes were present in 78% of the HGPS cohort, with a mean time to onset of 1.9 months. However, the skin findings were found in 24% of patients at birth, as in our patient. (5) The abdomen was the most commonly involved region (present in 83% of patients), followed by the bilateral lower extremities (48%), chest (14%), back (7%), and bilateral upper extremities (3%). Note that biopsy of sclerodermoid skin is nondiagnostic. Therefore, if HGPS is suspected, patients should be referred for genetic testing.Additional dermatologic abnormalities that may present initially include prominent scalp and body veins, which were seen in 59% and 22% of the Rork et al (5) HGPS cohort, with a mean time to onset of 5.4 and 3.1 months, respectively. Dyspigmentation and circumoral cyanosis were present in 16% and 22% of patients, with mean time to onset of 2.0 and 2.4 months, respectively.Another characteristic finding is loss of scalp hair, eyebrows, and eyelashes. Hair is present at birth but progresses at an early age to near-total alopecia. Scalp hair loss was found in 100% of patients with HGPS, with a mean time to onset of 10.2 months. Thus, it is an extremely reliable indicator of disease. Eyebrow and eyelash hair loss were present in 81% and 97% of patients with HGPS at birth, respectively. The characteristic pattern of hair loss consists of early alopecia of the occipital and temporal scalp, with hair on the mid-scalp and vertex being the last to fall out. (5) There is progression to loss of eyebrows and eyelashes, ultimately leading to near-total alopecia. Patients may also have dystrophic nails.Extracutaneous disease manifestations may include decreased postnatal growth, osteolysis of bones formed by membranous ossification with increased fracture risk, and lipodystrophy. These manifestations lead to increased risk of hip dislocation and a lack of body fat. Ophthalmologic features, including corneal dryness, corneal clouding, and exposure keratitis, may be present. Cardiovascular sequelae such as stroke and myocardial infarction represent the most common cause of death for patients with HGPS due to severely accelerated atherosclerosis. Paradoxically, lipid profiles commonly lack clear abnormalities in these patients. Finally, patients may also present with dental crowding and decay, a high-pitched voice, hypoplastic nipples, low-frequency conductive hearing loss, and/or absence of ear lobes. (5)(7)(8) Although our patient presented with mild developmental delay, cognitive development is typically normal in patients with HGPS. (8) In addition, patients with HGPS commonly present with more significant growth delays and failure to thrive than what was found in our patient.Lonafarnib is a farnesyltransferase inhibitor and the first treatment approved by the Food and Drug Administration (FDA) for treatment of HGPS and some progeroid laminopathies. (9) Approved in November of 2020, lonafarnib prevents farnesylation, a step integral to the formation of progerin. Treatment with lonafarnib has been shown to increase the lifespan of affected individuals by an average of 2.5 years, which represents an almost 20% increase in lifespan for these patients. (9) A currently ongoing phase I/II clinical trial is examining the use of lonafarnib in combination with everolimus, an immunosuppressant drug thought to assist in removal of the abnormal progerin protein (NCT02579044). One study by Koblan et al (10) demonstrated the use of adenine base editors and their ability to repair the dominant negative mutation associated with progeria in both mouse models and fibroblasts from children with progeria. Although further study in humans remains necessary, this highlights the potential utility of gene therapies in the treatment of progeria.In addition, treatment of specific disease manifestations is essential to reducing morbidity and improving quality of life for patients with HGPS. Diet modifications, including frequent, smaller-sized meals, are recommended. To avoid dental crowding, primary tooth extractions after eruption of the secondary tooth may be beneficial. Patients affected by hip dislocation due to HGPS should be managed with physical therapy and body bracing. Recommendations to reduce the impact of patients' lack of body fat include physical therapy, occupational therapy, hydrotherapy, and muscle-building exercises, in addition to shoe pads. (7) Cardiovascular and central nervous system complications may be treated with anticoagulation as necessary. In these cases, low-dose aspirin of 2 to 3 mg/kg may be of benefit to prevent cardiovascular and stroke sequalae. (7) In addition, sun protection should be applied on all exposed regions of skin before outdoor activities. Hearing aids should be encouraged for patients experiencing conductive hearing loss. Educational accommodations should be made on an individual basis.Finally, regular screening is particularly important in this patient population and includes carotid duplex ultrasonography, annual electrocardiography, echocardiography, and head and neck magnetic resonance imaging/magnetic resonance angiography. Patients should also have regular ophthalmologic, dental, neurologic, and audiologic examinations. Patient counseling should emphasize the need to avoid dehydration and limit physical activity because high-impact sports may precipitate hip dislocation. (7)After genetic testing and diagnosis of classic HGPS, the patient was started on lonafarnib therapy. Her disease course has been complicated by a fracture of the right distal radius and development of mild lagophthalmos and mild hyperopia. She continues to be on treatment with lonafarnib (50 mg twice daily). She also takes a daily aspirin (81 mg) and follows closely with a variety of specialists, including genetics, cardiology, and ophthalmology (Fig 2B).In patients presenting with syndromic features, a thorough skin examination can help expedite timely and accurate diagnosis.Dermatologic changes may precede other clinical findings of Hutchinson-Gilford progeria syndrome (HGPS) and most commonly consist of sclerodermoid skin changes, prominent veins, and progressive alopecia.The differential diagnosis for sclerodermoid skin changes in a young patient should include HGPS.Refer patients to genetics if HGPS is suspected because biopsy of sclerodermoid skin is nondiagnostic.