ARC Journal of Diabetes and Endocrinology

AUTHOR DETAILS

Amir M. I. Babiker^1,2

Assistant Professor, Consultant Paediatric Endocrinologist
Nasir A.N. Al-Jurayyan^1,2
Professor, Consultant Paediatric Endocrinologist
Hessah, M.N. Al Otaibi^1,2 Consultant Paediatric Endocrinologist
¹Division of Paediatric Endocrinology,
²Department of Paediatrics, College of Medicine and King Khalid University Hospital,
King Saud University, Riyadh, Saudi Arabia
[email protected], [email protected], [email protected]

Abbreviations: AG – Ambiguous genitalia; DSD – Disorders of sex development; KKUH – King Khalid University Hospital

What is known?
1. Ambiguous genitalia (or as better named disorders of sex development (DSD)) can occur because of endocrine causes (commonest) and non-endocrine causes (such as part of congenital malformations).
2. Clinicians should apply a thorough approach of history taking and physical examination in order to identify, and accordingly investigate, the possible cause of DSD on individual basis.
What is new?
1. DSD may be frequently associated with localised congenital malformation as reflected in our data over two decades. This higher risk of congenital malformation, we observed in our cohort, could be due to living in high altitudes in some parts of the Middle East, e.g Saudi Arabia, and also because of high incidence of consanguineous marriages.
2. Even rare new entities may be encountered in this part of the world such as: Reminiscent of hydrolethalus and pseudotrisomy 13 syndrome, which was previously reported also from our centre. Clinicians should pay attention to this, to avoid unnecessary long list of investigations of DSD, and to be able to report on new entities.

INTRODUCTION

Disorders of sex development (DSD) or differences of sex development, also sometimes referred to as disorders of sex differentiation are medical conditions in which the development of reproductive system is affected from even before birth through infancy to young adulthood [8]. More specifically,
. DSD refers to "congenital conditions in which the development of chromosomal, gonadal, anatomical sex is atypical" [18]. There are several types of DSDs with variable effect on the external and internal reproductive organs (Table 1).

Table1

Congenital anomaly of the genitalia is a medical term referring to any physical abnormality of the female or male external genitalia present at birth. This is a broad category of conditions. It is a complex medical and social emergency that can create social problems for the child and the family. For this reason, a team of experienced specialists, including neonatologist, geneticist, endocrinologist, paediatric surgeon or urologist, psychologist and social worker should be involved. As a consequence, a life-threatening condition such as adrenal crisis can arise in some conditions, and therefore early recognition is crucial [1, 5, 14, 24].
Since the spectrum of congenital genital anomalies is really broad, a detailed history and physical examination are essential. This would include a family history, e.g. any similar problem or miscarriage, stillbirth or neonatal deaths or infertility. Certain drugs can cross the placenta and interfere with organ development; hence, drug history is also important. Physical examination should concentrate on the description of the genitalia, anorectal structure, any midline defects, hyper pigmentation, and any other congenital anomalies of other parts of the body in a recognisable pattern. Some genital anomalies-like features may simply represent the extremes of prematurity [4, 10, 15, 16, and 17].
This study aims to highlight and express the importance of including other non-endocrine causes as important differential diagnoses in the management of DSD.

MATERIAL AND METHODS

The study group comprised all patients presented for the endocrine and paediatric clinics at King Khalid University hospital (KKUH), Riyadh, Saudi Arabia, over 21 years period (1989-2010) with disorders of sex development. KKUH hospital is one of the main referral hospitals in Riyadh, which receives approximately 5500 deliveries per year on average. Ambiguous genitalia (AG) was considered when there was difficulty in determining the sex on initial examination or when the external genitalia showed significant structure deviation from normal in an apparent male or female patient. The appropriate diagnostic (radiological and serological) tests were done for all patients in our study [4, 5].

RESULTS

During the period under review, a total of 98 patients were evaluated for AG, their age ranged between 1 day and 8 years. Sixty-nine (70.4%) patients were genetic females (46XX), while twentynine (29.6%) patients were having a male genetic sex (46XY) (Table 2).

Table2   Table3

The majority of patients had congenital adrenal hyperplasia (Table 3). Various 15 (15.2%) patients with congenital anomalies were diagnosed among different series of patients, four with isolated cloacal anomalies, two with isolated hypospadias, one with Prader Willi syndrome, one with Klinefelter's syndrome, two patients were mosaic Turner, two with clitromegally, two patients with multiple congenital anomalies observed in reminiscent of hydrolethalus and pseudotrisomy 13 syndrome, and finally one male patient with extreme prematurity (Gestational age- 24 weeks) (Table 3). Investigations revealed 46XY in the latter patient with gonads within the inguinal area and all hormonal investigations were normal. Eventually the gonads descend with phallus enlargement when his prematurity was corrected. Only two patients were evident to have true hermaphroditism by laparoscopic examination and biopsy (Table 3).

DISCUSSION

Reviewing the wide variety of congenital genital anomalies, it is obvious that the pathology is complex, diagnosis is difficult and in most situations a long treatment is required. The physicians are not always able to establish the diagnosis immediately after birth and a time and resources consuming investigations are requested. The majority of our cases, either 46XX or 46XY, were abnormally associated with clear endocrinopathy such as congenital adrenal hyperplasia (CAH) or androgen insensitivity syndrome, however, in others there seemed to be no rule [1,3-5,10,14-17,23,24]. In our study, ambiguous genitalia (AG) were associated with localised congenital malformation of the lower gut and urinary system in four patients. Similar results have been reported before from Saudi Arabia [2, 3]. This can be due to variable factors including higher risk of congenital malformation due to living in high altitudes in some parts of the country and also because of high incidence of consanguineous marriage [19, 22]. In a study from a high altitude area in Saudi Arabia, a prevalence of 72 cases per 10,000 deliveries of congenital malformations was reported. About 20% of the anomalies were urogenital [11]. A high incidence of congenital anomalies has also been reported in Western Saudi Arabia. In 5356 of born babies (2004-2005) in a large university hospital, 174 (27.06/1000) live birth and 13 (2.39/1000) stillbirth had congenital anomalies, and parents were consanguineous in 38.8% of cases [6]. Among the most common systems involved, in that study, were the external genitalia (2.8/1000) and urinary system (2.6/1000) [6].
In general, urogenital sinus and cloacal anomalies are rare. During development in utero, the genitourinary and intestinal tracts initially form together. As development progresses, the genito-urinary bladder, vagina and genitalia are separated from the bowel and intestinal tract by formation of the urorectal septum. In females, the bladder and urethra separate from the vagina [12, 13]. Multiple congenital anomalies following the pattern of certain genitalia syndromes has been observed as in reminiscent of hydrolethalus and pseudotrisomy 13 syndrome [9]. Pavone et al reported on unbalanced translocation of 46XYt (7; 16) [20]. As well, different series of ambiguous genitalia were reported in Klinefelter, Turner and Prader Willi syndromes [7]. Congenital genital malformations with Smith-Lemli Opitz syndrome may include severe underdevelopment of genitalia and/or female appearing external genitalia [21].
There are several literature reports of mosaic Turner patients associated with ambiguous genitalia secondary to the presence of SRY gene. Al Mulhim et al reported in his series two cases of mosaic Turner genotype, one of them had the SRY gene [2].
One of our patients was extremely premature. With the recent and rapid advancement of technology, neonatal services improved a great deal and therefore we will see more premature babies, possibly with incomplete development of genitalia

CONCLUSION

Pleural and pericardial effusions are rare but recognized complications of thyrotoxicosis and Graves' disease and should be considered in patients who present with dyspnea, atrial fibrillation.
So we suggest that Grave's hyperthyroidism should be considered in the differential diagnosis of pleural effusion in patients with thyrotoxicosis and analysis of more case is needed to better understand the underlying pathophysiology of this association.