Newborn infant with congenital lentigines as a manifestation of Carney Complex

Abstract

Carney Complex (CNC) is a rare syndrome characterised by skin pigmentation, endocrine over activity and myxomas, with the median age of detection being 20 years. We present a case of CNC diagnosed in infancy after being noted to have multiple lentigines over his face, abdomen, back and thighs at birth. We consider the differential diagnoses of similar cutaneous presentations in the well neonate and review the prognosis and suggested surveillance of patients with CNC.

Background

Lentigines are discrete, small, dark brown/black, oval or circular macules that are seen on the skin or mucous membranes. Lentigines seen at birth are classed as ‘simple’ and do not darken on exposure to sunlight, in contrast to the ‘solar’ lentigines seen in adults.¹ Recognition of these lesions can be a clue to underlying conditions, some of which carry an increased risk of neoplasia.² We present a case of a newborn infant with lentigines, with early recognition and genetic confirmation of Carney complex (CNC), which is infrequently diagnosed in the newborn period. We believe this case highlights the importance of considering such diagnoses in a neonate with congenital lentigines.

Case presentation

This boy was born in good condition at term by normal delivery, with a birth weight of 4.09 kg and a head circumference of 36.5 cm, demonstrating symmetrical growth with both his measurements close to the 91st centile. He was noted to have around 20 small dark brown macules over his face, abdomen, back and thighs at birth. Two small blue naevi were also noted on the left upper thigh, prompting further investigation (see figure 1). There was no relevant family history of note.

Figure 1.

Colour images A–D. (A) Close-up image of discrete lentigine. (B) Lentigine distribution over back. (C) Lentigine distribution over abdomen. (D) Blue naevus and lentigines on thigh.

Investigations

To help identify the nature of the pigmented lesions, a review by a dermatologist was arranged. The lesions were identified as congenital lentigines, either as a benign isolated finding, or a manifestation of an underlying genetic condition. The initial differential diagnoses considered were LEOPARD syndrome (lentigines, electrocardiographic (ECG conduction defect, ocular hypertelorism, and pulmonary stenosis, abnormality of genitalia, retarded growth and deafness) and LAMB syndrome (lentigines, atrial myxoma, mucocutaneous myxoma and blue naevi). LAMB syndrome is now accepted to be encompassed within CNC.³ In view of these suspicions, an ECG and echocardiogram were performed, which were normal. Hearing screening was satisfactory and an ophthalmology review confirmed a normal eye examination. Both of these findings were not suggestive of LEOPARD syndrome.

CNC is associated with endocrine abnormalities, and therefore, cortisol, prolactin and thyroid function were performed, which were all within normal limits.

He remained well and was discharged home with paediatric and genetic outpatient follow-up arranged. Genetic testing did not identify a causative variant for LEOPARD syndrome. A pathogenic mutation in the PRKAR1A gene was identified (c.549+1G>A splicing variant, heterozygous), confirming the diagnosis of CNC.

Differential diagnosis

Congenital lentiginosis should prompt consideration of Peutz-Jeghers syndrome (PJS), LEOPARD syndrome, PTEN hamartoma tumour syndromes, benign lentiginosis and CNC.

PJS, with a quoted prevalence of around 2.2/100 000, is the most well-known congenital lentiginosis with predisposition to malignancy.⁴ It is characterised by mucosal dark blue-brown hyperpigmentation and intestinal hamartomatous polyps. Pigmented lesions typically appear on the lips and buccal membranes.⁵ This was not seen in our case.

LEOPARD syndrome was initially suspected in our case. This syndrome is associated with lentigines typically over the trunk, neck and face, which would be in keeping with our patient. Facial dysmorphism including low set ears, downward slanting palpebral fissures and hypertelorism may be present. Cardiac anomalies include pulmonary stenosis and obstructive cardiomyopathy.^{6 7} As cardiac, hearing and ophthalmology assessments were normal, LEOPARD syndrome was unlikely in this infant.

‘PTEN hamartoma tumour syndromes’ includes Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) resulting from mutations in the tumour suppressor gene PTEN. Lentigines typically occur on the penis and vulvae. BRRS is also associated with hypotonia, seizures, macrocephaly and developmental delay.⁴ None of the above was seen in this infant.

‘Benign lentiginosis’ encompasses patterned lentiginosis, with autosomal dominant transmission of lenitigines on the face, lips, extremity, buttocks, palm and soles. Centrofacial neurodysraphic lentiginosis is also autosomal dominantly inherited and is associated with facial lentigines and developmental delay.⁴

CNC is infrequently diagnosed at birth. Lentigines may, however, be seen in the neonatal period with predisposition to the face, lips, genitalia and mucosa, as well as the trunk and extremities, as seen in our case. Blue naevi can also be present in around 40% of cases, two of which were seen in our patient, as seen in figure 1D.^{3 8} Presentation in this case was most suggestive of CNC, which was confirmed on genetic testing.

Outcome and follow-up

This boy is now 2 years old and is thriving with appropriate neurodevelopment and no evidence of endocrine overactivity or cardiac involvement. His follow-up consists of yearly cardiology, endocrine review and annual testicular ultrasound scan, along with regular general paediatric follow-up for skin surveillance and growth monitoring.

He developed a small wart like appendage on his left hemiscrotum at 18 months of age, and he is awaiting excision of this. Cutaneous myxomas are a feature of CNC, and are usually seen on the eyelids, ear canal, nipples and genital region.^{8 9} There was no suggestion of atrial myxoma on echocardiography.

In around 75% of boys with CNC, there is a predisposition to developing benign testicular tumours, particularly large cell calcifying Sertoli cell tumours, which occur in around half of men with CNC.^8–10 In our patient, testicular ultrasound performed at 8 months revealed a discrete hyperechoic fleck within the right testis suggestive of calcification. The significance of this is uncertain, as repeat scanning revealed that the hyperechoic area was no longer present.

Genetic mutations of the PRKAR1A gene were not detected in either parent, and the family have been counselled regarding the risk of recurrence being around 1% due to the possibility of germline mosaicism.

Discussion

CNC was first described in 1985, as ‘the complex of myxomas, spotty pigmentation and endocrine overactivity’.¹¹ CNC incorporates previous descriptions of a constellation of manifestations, including nevi, atrial myxoma, myxoid neurofibroma, ephelides syndrome and LAMB syndrome.³ It is a rare multiple endocrine neoplasia syndrome with a spectrum of manifestations. It is inherited in an autosomal dominant fashion, or by de novo mutations or deletions of the PRKAR1A gene located at 17q22–24 coding for the regulatory subunit type I alpha of protein kinase A (PKA, cAMP-dependent protein kinase) enzyme, known as the CNC1 locus, in up to 80% of patients. A second more infrequently encountered and less well understood locus (CNC2) at chromosome 2p16 is also known to be affected.^{8 10} Presently more than 140 mutations have been reported, most of which are unique mutations.¹² Prevalence is uncertain, with previous reports showing approximately two-thirds were women and around one-third are man.¹³

According to the criteria proposed by Correa et al, two major criteria confirmed with histology, imaging or biochemical testing, or one major criterion associated with one supplemental criterion is required for diagnosis (see figure 2).⁸

Figure 2.

Mono image. Diagnostic criteria for Carney complex (CNC). Source: Correa R et al.⁸ LLCSCT, large cell calcifying Sertoli cell tumour.

CNC phenotypically presents itself over years, affecting a number of systems. Skin manifestations are the most common, with lentigines occurring in 70%–80% of cases, blue naevi in 40% and cutaneous myxomas in 30%–50%. As demonstrated in our case, the location and associated features of the lentigines can help differentiate between the causes of lentiginosis (see figure 3).

Figure 3.

Mono image. Comparison of features of conditions associated with congenital lentigines. Adapted from: Lodish MB and Stratakis CA.⁴ LEOPARD, lentigines, electrocardiographic (ECG) conduction defect, ocular hypertelorism, and pulmonary stenosis, abnormality of genitalia, retarded growth and deafness. AD, autosomal dominant. GI, gastrointestinal. PPNAD, Primary pigmented nodular adrenocortical disease. GH, growth hormone; IGF1, insulin-like growth factor1.

Cardiac myxomas are seen in 20%–40%, and complications of these are the leading cause of death (over 50% of fatalities), with the median age of detection at 20 years of age. The average life span is 50–55 years, but appropriate surveillance aims to detect life-limiting conditions, to allow for normal life expectancy.^{3 8}

The most common endocrine tumour associated with CNC is primary pigmented nodular adrenocortical disease (PPNAD), affecting 25%–60%, predominantly females, resulting in excess production of cortisol, largely presenting in the second and third decades of life.^{8 11} A short synacthen test performed in in this infant was normal.

Pituitary manifestations include asymptomatic elevation of growth hormone (GH), insulin-like growth factor 1 or prolactin, and acromegaly secondary to pituitary adenoma in around 10% of patients. Therefore, growth monitoring and assessment of pubertal staging is important. Thyroid manifestations include thyroid nodules in up to 60%, often appearing in childhood as benign adenomas, cystic or nodular disease, or less commonly thyroid carcinoma.⁸

As mentioned previously, testicular manifestations including LCCSCTs carry a risk of infertility, hence the ongoing surveillance with ultrasound is required.⁸ These tumours are uncommon in the paediatric population, and are usually attributed to endocrine neoplasm syndromes like CNC and PJS.¹⁴

Surveillance in CNC mainly focuses on echocardiography (for cardiac myxomas), growth and pubertal stage monitoring (for endocrine neoplasms or abnormalities), testicular examination and skin evaluation. Recommendations include:^{8 15}

1. Annual echocardiography.

2. Regular skin evaluation.

3. Monitoring serum GH, prolactin and and IGF1 in early adolescence.

4. Regular thyroid gland examination and ultrasound if required.

5. Imaging can include CT for the detection of PPNAD; pituitary MRI, MRI of brain, spine, chest, abdomen, retroperitoneum and pelvis for the detection of psammomatous melanotic schwannoma.

6. Testicular examinations with ultrasound at least annually. (We suggest baseline imaging soon after diagnosis, as performed in our case, for future comparison).

7. Transabdominal ultrasound of ovaries in females.

8. Close monitoring of linear growth and yearly pubertal staging.

To conclude, CNC is infrequently detected in the newborn period. Detailed family history should be taken, as most conditions associated with congenital lentiginiosis have autosomal dominant inheritance. Systematic examination should be performed to identify associated abnormalities. Growth should be assessed, as macrocephaly may point towards PTEN hamartoma tumour syndromes. ECG should be considered to screen for conduction defects (LEOPARD syndrome) or structural anomalies. Failed hearing screening should also point towards the sensorineural hearing loss of LEOPARD syndrome. Development of cutaneous myxomas or evidence of endocrine overactivity should prompt consideration of CNC. By considering these diagnoses early, appropriate surveillance can be put into place, which may lead to improvement in life expectancy.

Learning points.

• This was a rare presentation of Carney Complex at birth, an already rare condition.

• Congenital lentiginosis may be benign, but should prompt consideration of an underlying genetic condition to allow for early surveillance to be initiated, which may help improve life expectancy.

• Careful family history taking, growth assessment and systematic examination for associated anomalies should be performed to guide further investigation.