Two cases of precocious puberty- Case 1

Two year old girl child brought with left breast enlargement for the last three months .
First born baby to an young couple delivered without any treatment of infertility after one year of marriage. All trimesters of pregnancy was uneventful , no medical illness , no pregnancy related problems . Except for iron tablets  and inj tetanus toxoid , no drugs taken by mother  .

 No family history of precocious puberty, disorders of sexual differentiation, bony problems ,early child death or prolonged medications ( suggestive of a familial endocrinology or syndrome association with precocity. Little bit of explanation about the relevance of above points. Few conditions of precocity have a high chance of inheritance. eg Congenital adrenal hyperplasia virilising types .Other entities like Mecune Albright syndrome basic problem is G protein mutation and hyper function of many endocrine organs out of which precocity is one. Skull and other bony problems are part of this entity .Hormonal medication of mothers are relevant for  evaluation of disorders of sexual differentiation in newborn baby , not much relevant in a case like this with onset of problems after such a normal gap ).

Baby was born at term by vaginal delivery , no resuscitation needed . No neonatal problems suggestive of hypoxia, meningitis, intracranial bleed. Her growth was normal and milestones in all fields of development proceeded normally . Precocity obesity  other hypothalamic /pituitary disorders may occur as a    sequelae of neonatal brain injury .
No history of head trauma, ear discharge, irritability, vomiting suggestive of raised intracranial tension .No recent behavioural changes, seizures, frequent falls or any other history suggestive of an associated neurological problem. Tuberculous meningitis ,  tuberculoma ,craneopharyngeoma are important organic entities behind precocity . One important entity to be kept in mind is hypothalamic hamartoma  , which presents in an interesting way ,gelastic seizures bout of laughter ,
When we take history one point to assess is the onset and course and evolution . Males are more likely to have organic reason underlying. Overall course progressing faster is likely to  have organic basis . Of course other neurological signs like visual field defect ,raised ICT etc always argue for underlying organic pathology . Many cases especially in females idiopathic. ( Experts in endocrinology may not agree with this point as what was considered idiopathic , actual pathogenesis is known now. Only point is i dont know these new advances

She is not on medications from any system . There was no features suggestive of hypothalamic disturbance like polyuria,somnolence , temperature regulation problems .
Immunization up to date.

The breast nodule is remaining almost same during these last three months. Apart from this swelling she did not have any other problem , active alert and playful.
She was worked up in a case by endocrinologist and was suggested to take leuprolide injection they thought of taking a second opinon before that , Hence she was with us

O/E
Her weight is 11 kg . expected for a 2 year old is 12 kg , as above 90 percent of expected.
Her length is  84 cm , expected length is 87 cm, ie a bit lower than normal. This point is very important in the analysis . Unlike when we take measurements  in a child with other medical problems  where we are interested on the lower side or normalcy (which is the situation in our country ) here in a case of suspected advanced sexual maturation we are interested in her height /length ,are they on the heigher side ? as  an advance in the length /height indicates  true precocity .
There are very few situations where we get precocity with normal or lower height . One of the main reason is hypothyroidism .(Peripheral hypothyroidism in a baby can rarely present with sexual precocity . You know why ?  When thyroid hormones goes down if the hypothalamo-pituitary system is normal it will try to compensate by producing more TSH (there can be elevation of gonadotrophic hormones also ). In this baby  her height was a bit on the  lower side. But she did not have any features of hypothyroidism . She was intelligent girl , no constipation , skin normal ,fontanels closed
No  dysmorphic features .
There was no neurocutaneous markers. Cafe au lait spot is relevent in two ways in precocity .
1. Part of neurofibromatosis
2. Maccune albright syndrome. Here she did not have any of the features of these Her head circumstance normal.
 No pallor, lymph node, rash, bony swelling, deformities .
There was breast enlargement on left side with palpable nodule 3 x 3 cm non tender .

Her system examination CNS and GIT normal ,

 Higher function, cranial nerve especially the field of vision and fundus normal . 

Abdomen examination did not show organomegaly or palpable mass. No bruit over abdomen or skull .Her SMR genital was prepubertal .One point relevant here is when we mention SMR always tell the status of genital hair , penile/testes and breast staging separte. There can be discordance in these which are very helpful to pin point the underlying pathology .Here in this girl genital examination showed no hair ,we did nt check the vaginal mucosa. clitoris was normal 

So at the end of clinical exam. what is our provisional diagnosis ? 

Isolated thelarche , YES most probably .which is very common and benign condition . 

Should we investigate at all ?  Yes. 

In fact we can adopt a policy to keep the patient under regular frequent follow up. May be one of the cheapest and simple investigation we can do is bone age assessment 

Investigations : already done from outside 

Counts, hemoglobin, peripheral smear was normal, urine routine normal, Mantoux negative 

Her growth card. 

Plotting leghth/ height over time is very important in the evaluation of precocity . Here we plotted today just one measurement . Changes in height  over time is not available. A growth card which shows a recent advance in the height /length , crossing percentile ( without corresponding change in weight ) is a point arguing for it. One time measurement also may help if it is interpreted with the mid parental height. Here height is not advanced. Weight also is below 50th centile . ( When we record the measurements always measure parents height and record mid parental height . 

Next very important investigation is X Ray hand 

In the evaluation always choose cheaper , non invasive simple ones. Plotting growth chart is the simplest and assessing the bone age the next. For assessing the bone age part to be chosen appropriately. One point is do not ask for wrist X-ray. Instead, always ask for X-ray hand ( This xray does nt show the tip of terminal phalanx ) Bone age is not assessed by looking at wrists only. This should be done more accurately by comparing with standard charts and taking in to consideration epiphysis of metacarpals phalanx also  

Here we compared it with charts and assessed bone age is 2.5. ie a bit advanced bone age . Her age is two 

So now ?

Till now we did nt have any reason for concern . Apart from a breast nodule which is a bit larger , no other indicators to suggest an organic problem to worry . 

But now, her bone age is a bit on the higher side. 

One question here. If she is having an advanced bone age, if it is due to influence of sex hormones why her height is not advanced? Which one is more dependable ? To depend on the normal height and not to go for higher investigations which are costly . 

Or ignore the normal height and give more weight to the advance bone age and go for costly investigations. 

What about the parents height? If they are short, whether the advance in the height masked by her inherent chance of familial trait of stunting ? This is just an argument. In this case both parents are tall above average . 

So what we should do?  

In a parent who can afford, in this scenario better to go ahead with hormonal assay. First FSH and LH . Depending on the level we will decide if the problem is central or peripheral and further investigations depending on their level.

In fact we need not worry about this point . This investigation was already done.

Here comes another confusion.

From the above chart there is no normal value for younger child 

If FSH, LH or both suppressed we need to investigate peripheral reasons ie exogenous introduction of estrogen hormones , ectopic ovarian or adrenal source.

If FSH/LH shows a high value that helps to exclude peripheral disorders as a reason  and we need to consider central causes only . 

In that case what is the cut off value of FSH /LH in this age group ?

 Is FSH high ? A value above 1 in a young child is to be considered doubtful . 

Is LH high? A value above 1 also to be considered significant. More important is LH /FSH ratio. A central hyperactivity.

Here again we are in confusion ; The FSH /LH ratio is not changed. FSH only is raised  , 

So what to do next?

We checked the values for children from standard charts. For that age FSH value can go up to 3.9 m iu/ml

So,

In summary,

Clinically it looks like isolated thelarche  and till few years back we ll take a decision just to  leave alone and follow up.

But few points we cant take it so lightly 

Bone age, advanced , even though minimally which can not be ignored 

Hormonal assay,  FSH is upper limit of normal and LH normal and Ratio is normal . That again creates bit of a confusion , but not strong enough to argue for a organic cause 

What to do?

Endocrinologist have advised Leuprolide . Can we take a stand not to give the drug without further investigation?

We have decided to Take MRI brain. If MRI is normal, keep the patient on regular follow up without any medication .

They will come for follow up with MRI next week. I shall update then.

19/05/2016

MRI was done today 

was normal . Decided to follow up