LEOPARD syndrome with rare skeletal anomalies: A case report

Sir,

A 15-year-old female patient presented to our outpatient department with complaints, since one year of a diffuse erythematous papular eruption, primarily in the butterfly distribution over face. The lesions commenced as red macules over the cheeks, progressed to involve the entire face and were associated with pruritus and photosensitivity.

General physical examination revealed height and weight below the third percentile. There were numerous light to dark brown, 2-10 mm diameter, macules distributed all over the skin and orogenital mucosae [Figure 1a]. Multiple pustular, scaly lesions over an erythematous base were seen on the face [Figure 2]. Genital examination revealed underdeveloped labia minora and labia majora with sparse pubic hair [Figure 1b]. Breast tissue was underdeveloped (Tanner grade III). Right thumb was hypoplastic with amputated left thumb. Left lower limb showed true shortening. Cardiovascular examination revealed loud S2 along with machinery murmur in the pulmonary area.

Figure 1.

(a) Hyperpigmented macules in oral mucosa. (b) Hypoplastic labia minora and sparse pubic hair

Figure 2.

Erythematous pustular lesions over the face

Electrocardiography was normal. Fasting blood sugar level, LFT, RFT and CBC were within normal limits. ANA was negative. X-ray left hip revealed shallow left acetabular head with superior migration of femoral head confirming the clinical impression of shortened left lower limb [Figure 3a]. Radiograph of the right wrist joint showed malalligned first metacarpals and phalanges whereas that of the left wrist showed absent first phalanges consistent with the history of amputation [Figure 3b]. Left-to-right shunt along with moderate sized PDA (4 mm) was detected on echocardiography. Audiometry revealed sensorineural deafness of the left ear. Ophthalmological examination revealed bilateral blepharitis and meibomitis.

Figure 3.

(a) X-ray hip; upward migration of left acetabular head. (b) Xray wrist; malalligned first metacarpals

Histopathological examination of facial skin [Figure 4a] biopsy showed findings consistent with rosacea, viz, mild hyperkeratosis and parakeratosis and intracorneal neutrophilic infiltration at one focus and intradermal localized small collections of epithelioid histiocytes, dilated telangiectatic capillaries and pigment incontinence. The skin biopsy from the arm [Figure 4b] revealed findings consistent with lentigo simplex. The patient's facial eruption responded to topical application of metronidazole gel twice a day and capsule doxycycline 100 mg once a day. She was counselled for PDA closure. Diagnosis of Leopard syndrome was established on the basis of above mentioned clinical and radiological findings.

Figure 4a.

Histopathology; The dermis showed intradermal localised small collections of epithelioid histiocytes, dilated telangiectatic capillaries, consitent with rosacea(H and E stain, × 100)

Figure 4b.

Histopathology; The epidermis shows increased number of melanocytes and melanophages in the dermis, consistent with lentigo simplex(H and E stain, × 100)

Leopard syndrome (LS) was first described by Zeisle and Becker in 1935. Similar cases were later reported by Moynahan and Walther, but it was Gorlin, in 1969 who coined the acronym.[1] It is an autosomal dominant disorder caused by a missense mutation in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located on chromosome 12q22. Characteristic features of LS included in the acronym are: L entigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, and Deafness. A diagnosis of Leopard syndrome may be established exclusively on the basis of clinical criteria.

LS is one of the so called neuro-cardio-facial-cutaneous (NCFC) syndromes, which include some overlapping disorders such as Noonan syndrome, neurofibromatosis type 1, Costello syndrome, cardiofaciocutaneous syndrome and Leopard syndrome itself, all caused by mutations in some components of the ras signalling pathway.[2] Patients do not usually present all the clinical features traditionally associated with the disorder. Indeed, several features are not present until late in life and do not clinically manifest until puberty. Lentiginosis the most frequently occurring feature, is observed in 100 percent of Leopard syndrome patients, followed by electrocardiographic abnormalities (80%), skeletal abnormalities (60%), hypertelorism (50%), short stature (42%), mental retardation (35%), abnormal male genitalia (29%), and deafness (27%).[3]

Musculoskeletal involvement leading to thorax anomalies like broad chest, pectus carinatum or excavatum is found in up to 75% of the newborns.[4] Mandibular prognathism, winging of the scapulae, scoliosis, joint hyper flexibility and other findings are less common.

To the best of our knowledge, this report of ours depicting the association of hypoplastic thumbs and true shortening of lower limb in a case of LS, is the first in English literature.