a case of bardet-biedl syndrome with hypogonadism

PROF.DR.G.SUNDARAMURTHY’S UNIT

DR.K.SENTHAMIZH SELVAN

A CASE OF HYPOGONADISM

CASE DETAILS

Balaji23 years Male kancheepuram

CLINICAL PRESENTATION

C/O delayed developmental milestones C/O diminished vision since childhood C/O poor development of genitalia

HISTORY OF PRESENT ILLNESS ----- patient had delay in attaining gross motor ,fine

motor,psycho-social and language milestones ----- From the age of 5 years patient had visual

disturbance ,which was progressive , not associated with

double vision,watering , pain or reddening of eyes patient had poor school performance and he was

a drop-out from 2 nd std. lost interest in games ,toys and surroundingsHe was not employed and did house hold

activities . At 22 years of age he presented with poorly

developed genitals no h/o penile erection,no early morning penile

tumescence , no h/o ejaculation

Had normal development of facial, pectoral, axillary and pubic hair .

No h/o seizures No h/o weakness of limbs H/o snoring + No h/o disturbances in sleep pattern. No h/o chest pain ,palpitation,

breathlessness No significant fever history

PERINATAL HISTORY: - no h/o drug intake by mother for any

ailments - no h/o fever or any other medical ailments

during pregnancy - born of normal ,vaginal delivery - no h/o prolonged labor - no h/o neonatal fever or seizures

FAMILY HISTORY : - Born of a 2 degree consanguinous marriage - other sibbling is normal - no other member in the family is having

similar complaints.

ON EXAMINATION

Patient was Conscious

Responding to oral commands

Afebrile

Hydration fair

Obese –BMI of 31kg/m^2 (ht =155 cms, wt=75 kg)

B/L gynaecomastia

Short neckShort neck

Ht : neck ratio of 14

Poly dactylyPoly dactyly

------ post axial

high arched palateFacial ,axillary and pectoral hairs are

present normally no pallor anicteric No cyanosis no clubbing no significant generalised lymphadenopathy no pitting pedal edema

Flat footFlat foot

BP: 110/80mmHg

Pulse: 84 /min ,regular

CVS: S1,S2 + nomurmur RS: NVBS + no added sounds P/A: soft,no HSM, BS+

GENITALIA: small sized penis, external urethral meatus normal, both testicles small sized – in the

scrotal sac pubic hair distribution –normal no varicocele

CNS : conscious responding to oral commands subnormal IQ divergent squint , vision – perception

of hand

movements pupils equally reacting to light

Optic fundus

Optic fundus

Ophthal opinion

media clear disc pallor bony spicules like structures consistent with

----RETINITIS PIGMENTOSA

ENT EVALUATION

--- B/L mild sensorineural hearing loss

No other cranial nerve involvement

motor system-N

sensory system-N

no cerebellar signs

no meningeal signs

problems

developmental delay learning disability strabismus retinitis pigmentosa mild sensorineural hearing loss obesity poly dactyly hypogonadism

INVESTIGATIONS

Urine: alb-nil sug –nil dep-1-2 pus cells CBC: Hb-10.4gms% TC-6400cells/cumm DC-P60/L38/E2 ESR-4/10mm RFT: blood sugar-110mgs% urea-38mgs% serum creatinine-0.9mgs% serum Na-144meq/dl K-4.8meq/dl

LFT:T.bilirubin- 1.2mg/dl direct-0.6mg/dl SGOT-44IU/L SGPT-86IU/L SAP-108IU/L T.protein-5.5gms/dl s.albumin-3.8gms/dl s.globulin-1.9gms/dl

LIPID PROFILE: s.total cholesterol- 210mgs/dl LDL-170mgs/dl HDL-40mgs/dl TGS-140mgs/dl

ECG- WNL

CHEST XRAY-NORMAL STUDY

ECHO : Normal study USG ABDOMEN : liver : 13.5 cm,spleen: 11.5 cms RK: 10.4×6.6cm LK: 9.3×4.8cm pancreas: normalUSG SCROTUM:Rt. Testis: 3×1.7×1.3cm

parenchyma Lt.testis: 3×2.1×1.6cm

normal cord,epididymis: normal tunica sac: normal

MRI BRAIN

IMPRESSION

----partially empty sella with compressed pituitary gland

HORMONAL ASSAY

TSH -2.050 (0.27-4.20 mIU/ml)

LH- 7.090 (1.7-8.6mIU/ml)

FSH- 11.05 (1.5-12.4mIU/ml)

Growth hormone -2.8 (0.5-17 ng/l)

Prolactin -6.12 (4.04-15.2ng/ml)

Testosterone- 0.19 (0.26-11.2ng/ml)

KARYOTYPING

------- done at IOG, Egmore

46,XY

FINAL DIAGNOSIS

“ BARDET-BIEDL SYNDROME WITH A

PARTIALLY EMPTY SELLA( PRIMARY) PRESENTING AS HYPOGONADISM”

 J Med Genet 1999;36:437-446

doi:10.1136/jmg.36.6.437 Original article “New criteria for improved diagnosis of

Bardet-Biedl syndrome”: results of a population survey

Primary features: Four features are required to be present of: Rod-cone dystrophyPolydactyly Obesity Learning disabilitiesHypogonadism in males Renal anomalies

Three primary plus two secondary features are required of:Secondary features Speech disorder/delay Strabismus/cataracts/astigmatism Brachydactyly/syndactyly Developmental delay Polyuria/polydipsia (nephrogenic diabetes insipidus) Ataxia/poor coordination/imbalance Mild spasticity (especially lower limbs) Diabetes mellitus Dental crowding/ hypodontia/small roots/high arched palate Left ventricular hypertrophy/congenital heart disease Hepatic fibrosis 

HYPOGONADISM IN OUR CASE

?

---probably due to primary gonadal failure,secondary to BBS per se

Case reports

The Laurence-Moon-Bardet-Biedl syndrome: unresponsiveness to the action of testosterone, a possible mechanism.

Mozaffarian G, Nakhjavani MK, Farrahi A. Abstract The pathogenesis of hypogonadism and hypogenitalism was investigated

in a male patient with the complete form of the Laurence-Moon-Bardet-Biedl syndrome. Synthetic gonadotropin-releasing hormone induced an increase in serum luteinizing hormone levels from 16.5 mIU/ml to 19.3 mIU/ml and in follicle-stimulating hormone levels from 18.5 mIU/ml to 25.9 mIU/ml. Serum testosterone levels were normal and did not rise after stimulation with human chorionic gonadotropin. The administration of thyrotropin-releasing hormone resulted in an increase in serum thyrotropin levels from 9.0 microU/ml to 12.0 microU/ml. Serum testoterone/estradiol-binding globulin, adrenocorticotropic hormone, and T3 resin uptake were normal. Serum cortisol showed a normal diurnal variation. The sex chromatin test was negative and the karyotupe revealed a 46,XY chromosome pattern. On biopsy, the left testis lacked germinal cells and the right testis showed spermatogenic arrest. Signs of hypogonadism and hypogenitalism persisted after 11 months of testosterone treatment. In this patient the target-organ unresponsiveness resulted in hypogenitalism and hypogonadism.

Empty sellae, impaired testosterone secretion, and defective hypothalamic-pituitary growth and gonadal axes in children with Bardet-Biedl syndrome.

Soliman AT, Rajab A, AlSalmi I, Asfour MG. Source Department of Pediatrics, Royal Hospital, Muscat, Oman. Abstract We evaluated growth parameters and hypothalamic-pituitary-gonadal and growth

functions in five children with Bardet-Biedl syndrome (BBS). Three of the five children had stature below the fifth percentile for age. Their growth hormone (GH) response to provocation was defective, and computed tomographic (CT) scanning revealed empty sellae in all of them. All the children were obese (body mass index [BMI] > 95th percentile for age). Three had hypercholesterolemia. Their basal serum testosterone concentration and testosterone response to 3-day human chorionic gonadotropin (HCG) stimulation were significantly lower than the levels in 12 age-matched obese normal children. Testosterone secretion failed to respond to HCG therapy for 4 weeks. Both basal gonadotropin levels (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and gonadotropin responses to LH-releasing hormone (LHRH) stimulation were normal and did not differ among the two study groups. It appears that primary hypogonadism is a cardinal feature of BBS, and it may be accompanied by hypothalamic and pituitary abnormalities.

DISCUSSION

Nomenclature: JZ Lawrence RC Moon Bardet

LMBBS Arthur Biedl

Cases reported by Lawrence and Moon --prog. spastic paraparesis and no polydactyly, obesity

Hence the term BARDET BIEDL SYNDROME

prevalence ---- 1 in 1,00,000 Mode of inheritance – 1) Autosomal recessive 2) Multi allelic

inheritance

--- individuals were homozygous /compound heterozygous for mutation at one locus but requires presence of a third heterozygous mutation to manifest phenotype

PATHOGENESIS OF BBS

BBS genes (14) BBS protein(basal body and cilia of

cells)

Assembled to form “BBSome”

Transports intracellular vesicles to base of cilia

plays vital role in ciliary function

CILIOPATHIES

Bardet –Biedl syndrome

primary ciliary dyskinesia

PCKD/Nephronophthisis

Alstrom syndrome

Meckel –gruber syndrome

EVALUATION AFTER DIAGNOSIS

Ophthalmic assessment : visual acuity,field,refractory errors and fundus

BMI Blood pressure pelvic examination and USG Renal function tests and Renal USG Urine analysis –to R/O nephrogenic DI Cardiac evalution-ECG,Chest X-ray,ECHO Developmental assessment

GTT

Lipid profile

Liver function tests

Thyroid function tests

otoacoustic emissions/audiometry

dental examination

neurological assessment

MOLECULAR DIAGNOSIS

14 genes – mapped till now mutations – 1) sequence analysis 2) targeted mutation analysis 3) deletion/duplication analysis

Implications

probands carriers pre-natal diagnosis

TREATMENT MODALITIES

Obesity – dietary mx, exercise, drug therapy for dyslipidemias Cognitive dysfunction,speech disorders – speech

therapy visual disturbances- low vision aids ESRD- renal transplantation In puberty – Hormonal assays and replacement

therapy Poly dactyly – removal of accessory digits cardiac abnormalities, diabetes – guidelines as that of

general population.

FOLLOW UP

6 monthly : urine analysis blood urea ,creatinine blood sugar annual : ophthal evaluation lipid profile,TFT,LFT renal USG`

PRIMARY ESSPRIMARY ESS SECONDARY ESSSECONDARY ESS

there is a hole in membrane covering pituitary gland,sub arachnoid space herniates and compresses pituitary

Incidental finding Hormones : N/mild

hyperprolactinemia no specific treatment

pit. Gland is damaged by tumour ,radiation or

surgeryPseudo tumour cerebri

can cause ESSHormones : deficient Requires replacement

EMPTY SELLA SYNDROME

THANK U