Johanson-Blizzard syndrome

In 1971 Johanson and Blizzard' reported a new syndrome in three unrelated girls characterised by congenital aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absent permanent teeth, and malabsorption. Children with this syndrome had been described earlier by Morris and Fisher in 19672 and Townes in 19693 as examples of trypsinogen deficiency disease. Townes and White4 subsequently reviewed the patient reported in 19693 and described the presence of additional features which confirmed the diagnosis of the Johanson-Blizzard syndrome. There have since been 22 patients reported with Johanson-Blizzard syndrome, and a further seven children related to these. The spectrum of associated features is now well documented and the inheritance of the syndrome is autosomal recessive. However, there remain many problems which make counselling difficult, in particular the degree of mental handicap and the observation that some children die from complications of the severe malabsorption despite intensive treatment. This article reviews the 22 patients previously reported and also includes details of a previously unreported boy.

reviewed the patient reported in 19693 and described the presence of additional features which confirmed the diagnosis of the Johanson-Blizzard syndrome.There have since been 22 patients reported with Johanson-Blizzard syndrome, and a further seven children related to these.The spec- trum of associated features is now well documented and the inheritance of the syndrome is autosomal recessive.However, there remain many problems which make counselling difficult, in particular the degree of mental handicap and the observation that some children die from complications of the severe malabsorption despite intensive treatment.This article reviews the 22 patients previously reported and also includes details of a previously unreported boy.

Clinical features
The main features are shown in the table.The most constant signs necessary to make a diagnosis are aplasia of the alae nasi, an exocrine pancreatic defect, and unusual hair growth pattern.
In the absence of major structural abnormalities, the affected infant usually comes to medical attention because of failure to thrive.On presentation, the infant is malnourished, hypotonic, and often oedematous because of hypoproteinaemia.be missed (figs 1 and 2).The picture is determined by the unusual nasal configuration.The severe aplasia of the alae nasi leads to the appearance of a  thin, torpedo shaped nose with large nostrils.In addition, the hair is swept up, especially frontally (fig 3), and has a patchy distribution over the scalp.
Closer inspection shows areas of alopecia (fig 4) with underlying aplasia cutis congenita, which are FIG 4 A small area ofalopecia in the occipital region.This child had an area ofaplasia cutis congenita.characteristically in the midline and in the occipital region.They heal to form atrophic scars.

MALABSORPTION
An exocrine pancreatic defect is a constant feature of this condition.Townes3 and Townes and White4 described the abnormalities of pancreatic function.
They reported an absence of trypsin, chymotrypsin, and their proenzymes, as well as carboxypeptidase and lipase, but they thought the amylase activity was normal.This was subsequently found to be a spurious result as isoenzyme studies showed the amylase was from the salivary gland.When the contribution from saliva is excluded, pancreatic amylase activity is absent.At necropsy the paren- chyma of the pancreatic gland is replaced by fatty 5 6 tissue.There are fewer islets of Langerhans but clinically there are no reports of impaired glucose tolerance.
The severe malabsorption caused by these en- zyme deficiencies leads to hypoproteinaemia, oede- ma, anaemia, and failure to thrive.The treatment of the pancreatic failure is by pancreatic enzyme replacement, as in cystic fibrosis.It is a life threatening condition and several of the children reported have died despite full medical treatment.

SHORT STATURE
The short stature has been attributed to hypothyroidism and malabsorption.There have been suf- ficient cases of short children with normal thyroid function4 6 7 to know that hypothyroidism is not the cause.A poor nutritional state contributes to the short stature and the child will not grow well unless the pancreatic enzyme deficiency is treated.
Our patient had pituitary hypothyroidism, but as yet has not had further pituitary function tests.It is interesting to speculate that growth hormone de- ficiency may be the cause of the short stature in this syndrome.In the two necropsy reports,5 6 there is no mention of pituitary gland pathology.HYPOTHYROIDISM All three girls in the original report of Johanson and Blizzard' were hypothyroid.They stated that the hypothyroidism may be aquired rather than con- genital, as one of their patients had a normal bone age at birth and her thyroid function was not as depressed as in the older patients.Subsequently six out of the 22 reported cases have been found to have reduced thyroid function.The results may be difficult to interpret because in severely mal- nourished children there will be depression of the thyroid binding globulin.The additional patient with the Johanson-Blizzard syndrome we present here had normal thyroid function, including a TRH test at the age of eight weeks.By the age of six months he had a low T4 (29 nmol/l) and low TSH (1.5 mU/l) indicating pituitary hypothyroidism.
The true aetiology of the hypothyroidism has not been determined.Thyroid autoantibodies are not present.At necropsy' the thyroid gland was atrophic with colloid distension in a child known to be hypothyroid, but normal6 in a euthyroid child.The growth failure, deafness, and mental retarda- tion have also been considered in terms of the hypothyroidism.However, there are sufficient chil- dren with normal thyroid function to know that hypothyroidism is unlikely to be the cause, though it can contribute if allowed to go untreated.

MENTAL RETARDATION
Thirteen out of the 22 children reported have been developmentally delayed.This is an underestimate as infants have died in the neonatal period.The cause is obscure.Daentl et al5 showed focal migrational defects in the brain at necropsy but this was not confirmed by Moeschler et al,6 who found the brain to be small but structurally normal.There is also no clear relationship between mental retar- dation and hypothyroidism.As pointed out by Moes- chler and Lubinsky,8 the patients of Schussheim et aP9 and Sismansis et al7 were severely retarded but neither microcephalic nor hypothyroid.The degree of retardation cannot be predicted.The patient of Day and Israel'o showed mild developmental delay and that of Townes" was reported as "relatively normal" at three and a half years, although by 121/2 years she needed special education.The brother and sister reported by Moeschler and Lubinsky8 were normal at two and a half and two years.Severe retardation was found in the patients of Daentl et al,5 Baraitser and Hodgson,'2 and Mardini et al. '3   ANORECTAL ANOMALIES As shown in the table, 11 of the reported children with the Johanson-Blizzard syndrome had anorectal abnormalities.In the majority of cases this was an imperforate anus.These children come to medical attention early and the inital surgical management is the fashioning of a transverse colostomy.It is important that poor weight gain in these infants is not attributed to the surgery but that malabsorption is recognised and treated.

DEAFNESS
Hearing loss has been reported in 12 out of 22 patients.The case of Sismansis et al7 was investi- gated in detail.There was a severe sensorineural hearing loss with associated absent vestibular func- tion, but the inner ears were structurally normal on polytomograms.There have been no further reports of more detailed radiological investigations.At necropsy6 the temporal bones were not studied.
Our patient has a symmetrical, moderately severe sensorineural hearing loss.

OTHER FEATURES
Additional features listed in the table are abnormalities of dentition, genitourinary anomalies, and cardiac malformations.The dental findings have been well reviewed by Zerres and Holtgrave.'4The children have delayed eruption of teeth, which are small but normal in shape.The genitourinary anomalies were striking in the three girls originally reported,' two of whom had a single urogenital orifice, but other children have not had major structural problems.A congenital heart defect has been reported in only three of the children, two of whom were sibs reported by Helin and Jodal'5 with situs inversus.Minor abnormalities of the lacrimal duct have also been recorded.

DIFFERENTIAL DIAGNOSIS
The diagnosis of the Johanson-Blizzard syndrome is not difficult when all the features are present.Hypoplasia of the alae nasi occurs in the ocu- lodentodigital syndrome,'6 aplasia cutis congenita of the scalp in the Adams-Oliver syndrome,'7 and pancreatic malabsorption in the Shwachman- Diamond syndrome, but these should not prove to be diagnostic problems.

Counselling
There is strong evidence for autosomal recessive inheritance.Affected sibs have been described by Moeschler  A more difficult problem in counselling is that of predicting the degree of mental retardation, the presence of severe structural lesions, and the success in treating the pancreatic exocrine defect.There have been no reports of prenatal diagnosis to date.At present one could offer a high resolution ultrasound scan in the hope of detecting the distinc- tive facial features and any structural abnormalities, such as the cardiac or urogenital lesions.

Prognosis
In the family of Mardini et al,13 all three patients died in infancy from complications of malabsorption and failure to thrive.The girl reported by Townes3   and Townes and White4 was still alive at the age of 12 years nine months.She had short stature, no permanent teeth, a sigmoidostomy because of an imperforate anus, and she required en- zyme supplements with her meals.She had mild mental retardation.If the pancreatic malabsorption problems are overcome the child can survive in- fancy, but is likely to require prolonged medical supervision.Even when given the best medical attention these children may develop severe prob- lems associated with hypoproteinaemia, namely infections and oedema, which can lead to death in childhood.
THE FACEThe diagnosis should be made easily in the neonatal period.Indeed the 'gestalt' of the Johanson-Blizzard syndrome is so distinct that seen once it should not Received for publication 6 May 1988.Accepted for publication 3 June 1988.

3 FIG 1
FIG 1 Ourpatient, a boy, aged two months.Note the small nose with aplasia ofthe alae nasi and the abnormal hair growth pattern, also shown in fig 3. 45

FIG 2 FIG 3
FIG2 Strikingly similarfacialfeatures are seen in this unrelated girl.