Malformation genetics

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Two % of all newborns have a congenital malformation. The parents often ask why this has happened, how it is treated, if there is a recurrence risk and what will happen in the future.

We study the molecular background of congenital malformations, especially disorders of sex development (hypospadias, uncertain sex at birth) and bladder exstrophy, when the child is born with an open urinary bladder. If the molecular diagnosis is determined the information about the child to the parents can be much better concerned further follow-up, prognosis and recurrence risk in the family. We also perform long-term follow up of adults that have been operated for these malformations and perform national register-based studies.

Research group leader:

Professor/senior physician

Agneta Nordenskjöld


Our projects concerns:

  • Molecular studies on DNA from families, mutation analysis of candidate genes in sporadic cases and families, arrayCGH and exome sequencing.
  • Clinical follow-up of adults with these diagnoses.
  • Register based studies on a national basis in order to identify different aspects of living with these diagnoses.

All results from these studies can easily directly be implemented in clinical practise.

On hypospadias

Hypospadias, is a form of disturbed sex development in boys, when the meatus urethra is situated on the underside of the penis or in the perineum. The incidence in Sweden is 1 of 125 boys (Skarin et al 2014). The treatment is surgical. Hypospadia is a complex malformation arising due to an interaction between gene and environment. In our group we have studied monozygotic twins and also brothers to hypospadiac boys and could conclude that growth restriction is a factor in the pathogenesis of hypospadias, since it is the smallest of the twin/ brothers that get hypospadias. We have shown that the incidence in Sweden has increased to 1 in 125 boys and without a known cause.

On disorders of sex development, DSD

The first question parents get after the delivery of a child is whether it is a boy or a girl. For about 10-20 parents each year this is not possible to say without an anatomical, genetic and endocrine investigation. This investigation is performed urgently by the DSD-team at the hospital. Lately, the knowledge on the molecular background of DSD has increased very much and the child´s sex is easier to identify. Parents, patients and patient organisations ask for long-term follow up studies to improve information.

Congenital adrenal hyperplasia, CAH

CAH is an autosomal recessive inherited enzyme deficiency causing a lack of cortisol and aldosterone as well as an increased level of androgens. This affects 1 in 10 000 children every year and some get severe symptoms directly after birth. Girls will get virilised genitalia often before birth. Earlier studies have indicated a tomboy play-behaviour in girls with CAH that is also correlated to the severity of the mutation. We have performed a long-term follow up study in adult women with CAH concerning postoperative results, fertility and psychosexual and psychosocial issues including QoL. We found that choice of occupation and hobbies are more masculine than in controls and also correlated to the severity of the mutation, same as in children. We have shown a lower degree of fertility due to different causes, and that these women give birth to less boys than girls, the ”sex ratio” is 25:75. Finally we showed that voice characteristics are affected in women with CAH and that has not been investigated before.

Bladder exstrophy

Bladder exstrophy is a rare malformation when the urinary bladder is not closed and the child is born with an open bladder in the lower part of the abdomen. In Sweden around 3 children ae born every year with bladder exstrophy. They often have to be operated several times during up-bringing and also have medical check-ups regularly. The molecular background is not known, there is however an increased risk among relatives speaking for a genetic background. We were the first to identify that a duplication on chromosome 22 (22q11) is increasing the risk for getting bladder exstrophy and that a few % of bladder exstrophy cases have that chromosome aberration and also an increased risk for hearing loss (Lundin 2010). We have also identified a de novo mutation in a patient with bladder exstrophy and shown the effect of this mutation in a zebrafish model with a malformed cloaca (Körberg et al 2015).