Multiple congenital defects in a young adult with features not limited to a syndrome A rare case report

Multiple congenital defects in a young adult with features not limited to a syndrome

A rare case report

Summary

We report the case of a 25-year-old female, presenting to the hospital with history of fever, cough and breathlessness of 3 days duration.  She was diagnosed to have congenital cyanotic heart disease in early childhood, but no intervention was done till date. She used to get recurrent respiratory infections which were treated as outpatient. On examination she is of short stature with kyphoscoliosis, having triangular face with retrognathia, hypertelorism, prominent epicanthal fold, low set ears, broad nose base and low posterior hair line. Her oxygen saturation with 4 litres oxygen was only 49%. She also had conductive deafness on the left ear. Patient’s genitalia and secondary sexual characters were well developed and her menstrual period last for 6-8 days with menorrhagia and dysmenorrhea. Other important features noted are cubitus valgus, pes cavus and systolic murmur suggestive of VSD. Echocardiography revealed dextrocardia, large VSD, pulmonary stenosis, double outlet right ventricle, right ventricular hypertrophy and transposition of great arteries. Ultrasonography revealed situs inversus and splenomegaly. Her ECG features were in favour of accelerated junctional rhythm. HRCT thorax to rule out bronchiectasis could not be performed as the clinical condition deteriorated rapidly and patient succumbed to her illness. This patient in spite of having multiple congenital defects that are fatal beyond infancy if not corrected lived up to 25 years. Not all her clinical features are limited to a known syndrome. Here we postulate that she had most of the features of Noonan syndrome or Noonan variant along with features of heterotaxy syndrome. A clinical syndrome with all these features is not so far reported in the literature.

Background

Noonan Syndrome (NS) is a relatively common congenital disease that affects both males and females equally. This is an autosomal dominant disorder with an incidence of 1 in 1000 to 2500 live births¹. This is caused by mutations in one of many genes such as PTPN11, SOS1, RAF1, RIT1, KRAS, NRAS, BRAF, and MAP2K1. The clinical features of NS include broad or webbed neck, low posterior hair line, typical chest deformity, short stature, ocular hypertelorism, epicanthal folds, triangula facies, micrognathism, kyphoscoliosis, cubitus valgus, pulmonary stenosis, ventricular or atrial septal defect and right ventricular hypertrophy.

Leopard syndrome is a Noonan Variant with features of hyperpigmented macules over the face and trunk (Lentigenes), electrocardiographic conduction defects, ocular Hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth and deafness.

Hetrotaxy syndrome has situs ambiguous or situs inversus. Situs ambiguous is a rare congenital defect where most organs are heterogeneously distributed in the chest and abdomen. In situs inversus, organs in the chest and abdomen are reversed. Paired organs may show isomerism. Isomerisms can be isolated, but can also be part of various syndromes, the best known of which—for its respiratory disorders—is immotile cilia syndrome, that includes Kartagener syndrome. This syndrome shows a recessive inheritance and is associated with situs inversus, heart defects, bronchiectasis, sinusitis, and otitis media as well as sterility in males².  Abnormal intestinal rotations are commonly found in patients with heterotaxy syndrome.^3,4 Heterotaxy can also cause polysplenia or asplenia associated with congenital heart defects. The heterotaxy syndrome associated with asplenia has a worse prognosis, because it is commonly associated with significant heart anomalies which include double outlet right ventricle, transposition of great arteries and ventricular septal defect.^5,6 However, the advances made in recent years in heart surgery and the early detection of heart disorders by prenatal ultrasonography have prolonged survival in patients with heterotaxy.^4,7

We report the case of a 25-year old adult female presenting with features of Noonan variant syndrome (Leopard syndrome) having additional features of Heterotaxy syndrome. This type of clinical presentation, which satisfies the diagnosis of both Leopard syndrome and Heterotaxy syndrome, is extremely rare and is not reported so far. More over this patient has congenital cardiac defects, which are not compatible with life if not corrected, and she has lived up to 25 years without surgical correction remains a mystery in clinical medicine.

Case presentation

A 25 year old female, from a low socioeconomic background, presented with complaints of fever, vomiting and increased breathlessness of 3 days duration. There is no history of cough with sputum production, orthopnea, PND, chest pain or palpitations. She gives history of recurrent chest infections since childhood. She also had left ear infections and bluish discoloration of hands and lips. There is no significant antenatal history, but her milestones were delayed and started walking at 7 years of age. She attained menarche at 16 years of age with regular cycle, associated with menorrhagia and dysmenorrhea. One of her maternal aunt had kyphoscoliosis and facial features similar to her. One child in her family died at 9 days of life.

She is short statured with a height of 146 cm and has clubbing and cyanosis. Her SaO2 is 49% on 4 ltrs. of O2. Other general physical features include widely set eyes, triangular face with broad forehead and micrognathia, broad nose base, low set ears, crowded teeth with gum hypertrophy, short and broad neck, low posterior hair line, hyper-pigmented macules over the trunk, kyphoscoliosis, cubitus valgus and pes cavus. Other features include asymmetrical chest, underdeveloped left mammary gland and precordial bulge. She has dextrocardia and situs inversus. Echocardiogram showed features of pulmonary stenosis, double outlet right ventricle, large VSD, right ventricular hypertrophy and transposition of great arteries. Neurological examination revealed conduction deafness on the left side. Ultrasound examination confirmed situs inversus and a large spleen.

Fig-1: Demonstrating the important clinical findings such as cyanosis (A), low posterior hair line (B) and thoracic kyphoscoliosis (C).Multiple hyper-pigmented macules are also seen on the back.

Investigations

Blood examination showed elevated total count with neutrophilic leukocytosis. ESR was 54 mm fall/1st hour. Platelet count was 1,18,000 cells/cmm.

X ray chest showed scoliosis of thoracic spine and dextrocardia. Stomach air bubble is not seen on the left side. ECG showed tachycardia and inverted P wave in all leads except aVR and V1. Echocardiographic features include situs inversus with dextrocardia, Double outlet right ventricle (DORV) with Transposition of grat arteries (TGA), subaortic ventricular septal defect (VSD), Pulmonary stenosis (TOF Physiology), dilated coronary sinus with SVC draining in to CS and normal biventricular function.

Ultrasound examination of abdomen revealed situs inversus with large spleen on the right side. Both kidneys were normal except increased echogenicity. Uterus and adenexia appeared normal.

Her renal function was altered with a blood urea of 88 mg% and serum creatinine of 3.2 mg%. Arterial blood gas analysis showed PaO2 24, PaCO2 30, HCO3 22 and a PH of 7.21

HRCT could not be performed to rule out Kartagener’s syndrome as the patient’s condition deteriorated rapidly.

Fig-2: X ray chest showed scoliosis of thoracic spine and dextrocardia. Stomach air bubble is not seen on the left side.

Fig-3: ECG showing tachycardia and inverted P wave in all leads except aVR and V1.

Discussion

Noonan Syndrome (NS) is a relatively common congenital disease that affects both males and females equally. This is an autosomal dominant disorder with an incidence of 1 in 1000 to 2500 live births¹. This is caused by mutations in one of many genes such as PTPN11, SOS1, RAF1, RIT1, KRAS, NRAS, BRAF, and MAP2K1. Noonan syndrome was first described in 1963 by Noonan and Ehmke⁹. It is also known by synonyms such as male turner syndrome or female pseudo turner syndrome. These patients were previously thought to have a form of Turner syndrome, with which Noonan syndrome shares numerous clinical features. Patients with Noonan syndrome have normal karyotypes to differentiate it from Turner syndrome. Classical Noonan phenotype has features such as short stature, short or webbed  neck, low posterior hair line, ocular hypertelorism, short nose with broad base, low set ears with posterior folding, triangular facies with small chin, padded fingers and toes, lymphedema, mental retardation, pulmonary stenosis, atrial or ventricular septal defects, hypertrophic cardiomyopathy and bleeding tendency. Rarely coarctation of aorta and tetralogy of Fallot (TOF) were also reported¹⁰. This patient has most of these features to satisfy the diagnosis of Noonan Syndrome. Presence of sexual characteristics with regular menstrual cycles rule out the possibility of Turners syndrome. We could not do karyotyping to establish mutations responsible for this syndrome.

There are few clinical features in this patient which cannot be explained by Noonan syndrome. These are multiple hyper-pigmented macules over the trunk (lentigenes), electrocardiographic conduction defect in the form of accelerated junctional tachycardia and conduction deafness. These features are described in Leopard syndrome which is a Noonan variant.  Leopard syndrome is a complex dysmorphogenetic disorder of variable penetrance and expressivity, first described by Zeisler and Becker in 1936¹¹. Gorlin et al introduced the acronym LEOPARD as the name of the syndrome in 1969¹² to highlight the main features of the disorder such as Lentigines (L), electrocardiographic conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), abnormalities of genitalia (A), retardation of growth (R) and deafness (D). Not all of the findings are present in any given patient. LEOPARD syndrome, also known as Noonan syndrome with multiple lentigines, is a rare autosomal dominant disorder most often caused by missense mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP2¹³.

Presence of dextrocardia, situs inversus, double outlet right ventricle and transposition of great arteries were never reported in Noonan syndrome or Leopard syndrome. These features make this patient unique in clinical presentation. It is very rare to see significant structural abnormalities of heart in dextrocardia with situs inversus. The structural abnormalities detected in this patient are all serious conditions with which patient cannot survive beyond infancy if not treated. This patient lived up to 25 years without undergoing any intervention is also unique. These features are explained in heterotaxy syndrome. Heterotaxy have been recognized since 1933 (complete) ¹⁴ and 1826 (incomplete)¹⁵. The habitual and orderly arrangement of the organs in the human body is determined early in the embryonic development and is based on genetic information¹⁶. The loss of such orderly arrangement may characterize situs inversus or a disordered and variable arrangement (heterotaxy syndrome). Heterotaxy syndrome has an approximate incidence of 1:10,000 births and is slightly more prevalent in men, at a ratio of 2:1.

Hetrotaxy syndrome has situs ambiguous or situs inversus.  Situs ambiguous is a rare congenital defect where most organs are heterogeneously distributed in the chest and abdomen. In situs inversus, organs in the chest and abdomen are reversed. Paired organs may show isomerism. Isomerisms can be isolated, but can also be part of various syndromes, the best known of which—for its respiratory disorders—is immotile cilia, that includes Kartagener syndrome. This syndrome shows a recessive inheritance and is associated with situs inversus, heart defects, bronchiectasis, sinusitis, and otitis media as well as sterility in males².  Abnormal intestinal rotations are commonly found in patients with heterotaxy syndrome. Heterotaxy can also cause polysplenia or asplenia associated with congenital heart defects. The heterotaxy syndrome associated with asplenia has a worse prognosis, because it is commonly associated with significant heart anomalies which include double outlet right ventricle, transposition of great arteries and ventricular septal defect.^5,6 At least 12% of primary ciliary dyskinesia (PCD) patients have heterotaxy.¹⁷ Cyanosis or poor peripheral perfusion is the most common findings in patients with heterotaxy. The liver may be on the left, rather than on the right, and it may span the abdomen. Dextrocardia may be identifiable. Other components of the syndrome include situs inversus totalis, dTGA, DORV, VSD, growth retardation and delayed milestones.

Conclusion

We report a rare case in a 25-year old female with a unique combination of clinical features. She has all clinical manifestations of Noonan variant- Leopard syndrome, and in addition has features of heterotaxy syndrome. Available literature did not show any similar case report. The cardiac defects are all serious and not compatible with life beyond infancy if not surgically corrected. This patient lived up to 25 years without any surgical correction. This syndrome may be called Leopard-Heterotaxy syndrome considering the clinical features of both Leopard syndrome and heterotaxy syndrome in one patient.

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