Background heart anomalies and hearing loss. The major

Background 

H syndrome is a rare systemic inherited
histiocytosis, with a prevalence of less than 1 /1000000. It is characterised
by typical cutaneous findings and associated systemic manifestations. The major
clinical findings are hyperpigmentation, hypertrichosis, hepatosplenomegaly,
heart anomalies and hearing loss. The major common
endocrine manifestations include hypogonadism, short stature and diabetes
mellitus.Due to overlapping
clinical features, H syndrome is now considered to include pigmented
hypertrichosis with insulin dependent diabetes mellitus syndrome (PHID),
Faisalabad histiocytosis (FHC) and familial sinus histiocytosis with massive
lymphadenopathy (FSHML). Here, we report 2 cases of  H-syndrome, both in paediatric age group and
both of which were proven using genetic testing.Discussion and Conclusion            H syndrome is a rare 
autosomal-recessive histiocytosis with characteristic cutaneous findings and
accompanying systemic manifestations systemic manifestations. The major
clinical and laboratory findings of hyperpigmentation and hypertrichosis, hepatosplenomegaly,
heart anomalies, hearing loss, hypogonadism, low height, and occasionally,
hyperglycemia1. A few patients have been reported from India 2,3. Males have been reported to have scrotal masses, gynecomastia, and
azoospermia 2, as seen in one of our case. Previous case reports
have revealed that testicular ultrasound examination showed echogenic
thickening of both the spermatic cords and the scrotal sac, with normal-sized
testes1. Other features that are described are varicose veins,
hallux valgus, fixed flexion contractures of interphalangeal joints. The
commonest among them are hyperpigmentation, phalangeal flexion contractures,
hearing loss, and short stature, seen in around 40% subjects. Insulin-dependent
diabetes mellitus and lymphadenopathy are found in around 20% of these patients3.
These patients develop progressive cutaneous hyperpigmented, hypertrichotic,
and indurated plaques over the lower limbs and lower abdomen during the first
or second decade of life, which is the hallmark for the diagnosis. However as
mentioned earlier in the case 1 this hallmark cutaneous pigmentation may be
subtle especially in patients with a darker skin complexion and may be missed
on a cursory physical examination. The waxing and waning of cutaneous
manifestation also hinders timely diagnosis.  The table below
shows the major clinical features in H syndrome that has been described and
their presence in our two patients.     

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Clinical features

Case 1

Case 2

Origin

Lakshadweep

Indian

Sex

Female

Male

Age at presentation

9

9

Location of cutaneus
manifestation

Thigh

Thigh

Genital masses

+

Micropenis

Gynecomastia

Varicose veins

Hepatosplenomegaly

Short Stature

+

+

Hypogonadism

Episcleritis /exophthalmos

Facial telengiectasia

Flexion contracture

Mental retardation

IDDM

+

+

Malabsorption

Flat foot / hallux valgus

Sensori neural hearing loss

+

+

Lympadenopathy

Hematologic

 Laboratory tests
will show an elevated erythrocyte sedimentation rate and CRP , mild microcytic
anemia, and elevated liver enzymes. Though liver enzymes were normal in our
patients, they had an elevated C Reactive protein and ESR.  Hypogonadism (hyper- or hypogonadotropic) and
azoospremia may be observed. Histopathologic examination of the involved skin
is characterized by inflammation, with seborrheic keratosis-like acanthosis in
the basal layer, histiocyte infiltration, and a perivascular mononuclear
infiltrate, with plasma cells and mast cells throughout the dermis and
subcutaneous fat1-3. These histiocytes are mainly CD-68 positive and
sometimes S100 positive8.                                                
Genetic analysis in our both patients revealed a reported homozygous
missense mutation, p.Arg134Cys, in the SLC29A3
gene 2. Mutations in the SLC29A3
gene were initially described to present as 2 allelic disorders- one was
a  diabetes-type pigmented hypertrichosis
with insulin dependent diabetes mellitus and second as deafness-type H syndrome4,5.But
both our cases had coexistant deafness and diabetes mellitus in addition to the
typical cutaneous manifestations. There are many other case series5,6  that has reported similar presentation,
contrary to the concept of discrete allelic disorders. Mutations in the SLC29A3 gene have also been found in Rosai-Dorfman
disease and Faisalabad histiocytosis, which has also been reported to have
immunophenotypic similarities such as positivity for CD68, CD34, and factor
XIIIa7. Till date, around 20 different mutations have been
identified in SLC29A3, with the majority
of them located in exon 62,3.But both the cases we have reported,
had a mutant SLC29A3 located in exon 4. The reason for the various
manifestations are still unclear but it might be probably because of hENT3
mutations that alter nucleoside pool and decrease ATP in mitochondria and
lysosomes perturbing their homeostatic functions9. The reason for
short stature and GH-IGF axis in this syndrome is yet to be explored.                         Till date, we could
find around 100 published cases of H syndrome ,around 80 of them with molecular
confirmation. This should be considered as a remarkable number for a relatively
novel autosomal recessive disorder, which implies that the disorder is not as
rare as it is thought to be. Conclusion

    Though it has been considered as a very rare disorder , we could
find as many as 100 case reports till date for a relatively novel disorder.
This syndrome is often being misdiagnosed or even undiagnosed and hence
unreported. The characteristic cutaneous manifestation along with genetic
testing , is the key to diagnosis. However, the subtle skin pigmentation and
its waxing and waning course delays timely diagnosis. The hearing loss also
varies in severity and can go unrecognised. It is possible that cases go
undiagnosed or are not diagnosed properly because of its overlapping features
with other syndromes. A timely diagnosis would however avoid unnecessary
investigations and help us look for the other components of this syndrome. 

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